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American Diabetes Association

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Alexandria, Virginia 22311

DOI: 10.2337/9781580404563

Library of Congress Cataloging-in-Publication Data

Medical management of type 1 diabetes.—6th ed. / Francine R. Kaufman, editor.

p. ; cm.

Medical management of type one diabetes

Includes bibliographical references and index.

ISBN 978-1-58040-456-3 (alk. paper)

I. Kaufman, Francine Ratner. II. American Diabetes Association. III.

Title: Medical management of type one diabetes.

[DNLM: 1. Diabetes Mellitus, Type 1. WK 810]

616.4’6206—dc23

2012009322

iv Medical Management of Type 1 Diabetes

Diabetes Standards and Education

Highlights

Philosophy and Goals

Glycemic Control and Complications: A Summary of Evidence

Dysglycemia and Complications from Population-Based Data

Goals of Treatment

Clinical Goals

Conclusion

Patient Self-Management Education

General Principles

Self-Management Education Process

Content of Diabetes Self-Management Education

Additional Topics of Importance for Type 1 Diabetes

Incorporating Patient Education in Clinical Practice

Conclusion

Tools of Therapy

Highlights

Insulin Treatment

Insulin Preparations

Treating Newly Diagnosed Patients

Insulin Regimens

Alternative Insulin Delivery Systems

Optimizing Blood Glucose Control

Common Problems in Long-Term Therapy

Insulin Allergy

Special Considerations

Conclusion

Treatment with Amylin Analog Pramlintide

Monitoring

Patient-Performed Monitoring

Glucose Sensors

Ketone Testing

Physician-Performed Glucose Monitoring

Other Monitoring

Conclusion

Contents v

Nutrition

Nutrition Recommendations

Nutrition Therapy for Type 1 Diabetes

100

Additional Nutrition Considerations

109

The Process of Medical Nutrition Therapy

113

Practical Approaches to Nutrition Counseling

115

Conclusion

117

Exercise

122

Glycemic Response to Exercise

122

Potential Benefits of Exercise

123

Potential Risks of Exercise

124

Reducing Exercise Risks

125

Exercise Prescription

127

Aerobic Training

127

Strategies for Maintaining Optimal Glycemic Control

with Exercise

130

Conclusion

131

Special Situations

133

Highlights

135

Diabetic Ketoacidosis

139

Presentation of DKA

139

Acute Patient Care

141

Other Important Considerations

145

Intermediate Patient Care

147

Preventive Care

148

Conclusion

148

Hypoglycemia

150

Pathophysiology

150

Mild, Moderate, and Severe Hypoglycemia

151

Common Causes of Hypoglycemia

153

Treatment

155

Hypoglycemia Unawareness

157

Hypoglycemia with Subsequent Hyperglycemia

158

Dawn and Predawn Phenomena

159

Conclusion

159

vi Medical Management of Type 1 Diabetes

Pregnancy

161

Risk Factors

161

Maternal Metabolism During Pregnancy

162

Preconception Care and Counseling

162

Congenital Malformations: Risk and Detection

166

Maternal Glucose Control During Pregnancy

167

Nutrition Needs

169

Outpatient Care

169

Timing of Delivery

171

Labor and Delivery

172

Postpartum Care

173

Family Planning and Contraception

173

Conclusion

174

Surgery

176

General Principles

176

Major Surgery

176

Minor Surgery

177

Conclusion

177

Islet Transplantation

178

Psychosocial Factors Affecting Adherence,

Quality of Life, and Well-Being: Helping Patients Cope

181

Highlights

182

Periods of Increased Emotional Distress

185

Maintaining Adherence

187

Diabetes Complications

188

Developmental Considerations in Children

189

Developmental Considerations in Adolescents

193

Adults

197

The Elderly

198

Emotional and Behavioral Disorders and Diabetes

199

Stress and Diabetes

200

Contents vii

Complications

203

Highlights

205

Retinopathy

209

Eye Examination

209

Clinical Findings in Diabetic Retinopathy

210

Evaluation

212

Treatment

214

Conclusion

216

Nephropathy

219

Clinical Syndrome

219

Natural History

219

Pathogenesis

221

Testing for Nephropathy

221

Management of Nephropathy

222

Hypertension

225

Other Aspects of Treatment

226

Dialysis and Kidney Transplantation

227

Conclusion

228

Neuropathy

230

Overview of Neuropathies

230

Distal Symmetric Sensorimotor Polyneuropathy

231

Late Complications of Polyneuropathy

232

Management of Distal Symmetric Polyneuropathy

and Complications

234

Autonomic Neuropathy

235

Focal Neuropathies

239

Conclusion

240

Macrovascular Disease

242

Prevalence and Risk Factors

242

Assessment and Treatment

243

Symptoms and Signs of Atherosclerosis

246

Conclusion

248

Limited Joint Mobility

251

Detection and Evaluation

251

Conclusion

252

Abnormal Linear Growth

253

Subtle Growth Abnormalities

253

Determining Growth Rate

253

Conclusion

254

A Word About This Guide

his is the sixth edition of Medical Management of Type 1 Diabetes. Originally

written as the Physician’s Guide to Insulin-Dependent (type 1) Diabetes: Diag-

nosis and Treatment, this book has been repeatedly revised to provide the

reader with the latest information on type 1 diabetes. This is just one of the many

books for clinicians published by the American Diabetes Association. Other titles

include Intensive Diabetes Management, Medical Management of Type 2 Diabetes,

Medical Management of Pregnancy Complicated by Diabetes, and Therapy for Diabetes

Mellitus and Related Disorders. This book has had an impressive list of previous edi-

tors, Mark A. Sperling, MD; Julio V. Santiago, MD (whose many contributions to

the field of diabetes will never be forgotten); Jay S. Skyler, MD; Bruce W. Bode,

MD; as well as many prestigious contributors who brought forward the necessary

information to advance the field and improve the outcomes of people with type 1

diabetes throughout the world.

I am particularly honored to be the editor since the fifth edition and to have the

opportunity to build on the work of so many others. The goal of Medical Manage-

ment of Type 1 Diabetes is to continue focusing on key areas, including important

clinical trials and the latest ADA Standards of Care. The first section is on Diagno-

sis and Classification/Pathogenesis of diabetes, and discusses the latest molecular

advances and strategies to influence the type 1 process. The Diabetes Standards

and Education section elucidates treatment goals and the importance of key areas

in diabetes self-management education. Tools of Therapy includes insulin regi-

mens, new agents to treat type 1 diabetes, advances in glucose monitoring, and the

contribution of lifestyle. The section on Special Situations deals with the salient

issues on treating and preventing DKA and hypoglycemia, as well as management

of pregnancy and surgery. Psychosocial Factors focuses on understanding barriers

and improving adherence, taking into account age, developmental factors, stress,

and emotional/behavior disorders. Complications lays out the latest strategies to

screen, treat, and prevent the organ system damage associated with diabetes.

This comprehensive guide to the clinical care of the patient with type 1

diabetes across the age spectrum, reveals that patients benefit from the effective

Acknowledgments

he American Diabetes Association gratefully acknowledges the contribu-

tions of the following health care professionals and members of the Asso-

ciation’s Professional Section to previous editions of this work:

Bruce W. Bode, MD; Lloyd P. Aiello, MD, PhD; Jerry D. Cavallerano, OD,

PhD; Paul C. Davidson, MD, FACE; Sandy Gillespie, MS, RD, LD, CDE; Char-

lotte Hayes, MMSc, MS, RD, CDE; Lois Jovanovic, MD; Philip A. Lowe, MD;

Stephen Pastan, MD; David G. Robertson, MD; Ronald J. Sigal, MD, MPH,

FRCPC; R. Dennis Steed, MD, FACE, CDE; and Deborah Young-Hyman,

PhD.

The Editor thanks the reviewers who aided in the review and critique of this

book, including M. Sue Kirkman, MD; Stephanie A. Dunbar, MPH, RD; and

Paulina N. Duker, MPH, APRN, BC-ADM, CDE.

xiii

Highlights

Diagnosis and Classification/

Pathogenesis

DIAGNOSIS AND

as the Diabetes Prevention Trial -

CLASSIFICATION

Type 1 (DPT-1) and the multina-

tional ŦrialNet study, have shown

n Diabetes encompasses a wide

onset can be indolent and early diabe-

clinical spectrum. The vast majority

tes can be relatively asymptomatic.

of cases of diabetes fall into two broad

etiopathogenetic categories:

n Approximately 1.89 per 1,000

• type 1 diabetes, the cause of which

children and youth have diabetes.

is an absolute deficiency of insulin

Over 80% of those children under the

secretion

age of 10 years, and the majority of

children between the ages of 10 and

• type 2 diabetes, the cause of which

is a combination of resistance to

19 years have type 1 diabetes. Inci-

insulin action and an inadequate

dence is similar in males and females.

compensatory insulin secretory

The percentages of type 1 diabetes

response

are highest in non-Hispanic white

youth, intermediate in Hispanics and

n Indications for diagnostic testing

African Americans, and markedly less

include

common in Asian Pacific Islanders

and American Indians. Type 1 dia-

• positive screening test results

betes has been increasing 3-4% per

• obvious signs and symptoms of

year in children and youth, and even

diabetes (polydipsia, polyuria,

more in young children under the age

polyphagia, weight loss)

of 5 years. It is estimated that in 2007

• an incomplete clinical picture,

about 16,000 youths developed type 1

such as glucosuria or equivocal

diabetes and 3,800 developed type 2

elevation of random plasma glu-

diabetes.

cose level or A1C.

n At presentation, patients with

n When diabetes is fully evolved,

type 1 diabetes can be any age and

fasting plasma glucose levels are

often have experienced significant

≥126 mg/dL (>7.0 mmol/L), random

weight loss, polyuria, and polydipsia

plasma glucose levels are ≥200 mg/dL

before presentation. The oral glu-

(>11.1 mmol/L), and A1C is ≥6.5%

cose tolerance test is rarely needed

(A1C elevation may not occur in the

to diagnose type 1 diabetes. Delayed

presence of certain hemoglobinopa-

diagnosis is a serious, sometimes

thies). Type 1 diabetes generally pres-

fatal, problem, especially among

ents with unequivocal hyperglycemia,

younger children.

although natural history studies, such

n Approximately 25% of children

ZnT8A, and insulin autoantibodies or

who present with newly diagnosed

IAA). This is followed over months to

type 1 diabetes are ill with diabetic

years by the progressive loss of insulin

ketoacidosis, those <2 years of age

secretion due to b-cell destruction,

are at highest risk, and may die from

particularly in those with persistent,

rapid metabolic decompensation and/

multiple autoantibodies.

or delayed diagnosis due to lack of

suspicion of diabetes.

n Fasting hyperglycemia occurs

when b-cell mass is reduced by

n Type 1 diabetes can develop at

80-90%. Typical symptoms of dia-

any age and is sometimes mistaken

betes, i.e., polyuria, polydipsia, and

for type 2 diabetes among adults who

weight loss, appear once hypergly-

may have a more gradual course of

cemia exceeds the renal threshold of

onset, including those with latent

~180 mg/dL (~10.0 mmol/L) glucose.

autoimmune diabetes, which is

referred to as LADA.

n After diagnosis and correction of

acute metabolic abnormalities, some

individuals experience a “remission

PATHOGENESIS

or honeymoon phase,” a temporary

period when there is preservation

n The primary defect in type 1 dia-

of endogenous insulin secretion as

betes is inadequate insulin secretion

determined by C-peptide levels, the

by pancreatic b-cells.

need for exogenous insulin is dimin-

n Genetic predisposition, which

ished, glycemic control is improved,

can be determined by the presence

and glycemic variability reduced.

of certain genetic alleles (HLA-DR/

Multiple interventions have been

DQ alleles can be either predisposing

tried to preserve b-cells, but none has

or protective), clearly plays a role in

been shown to be effective in revers-

the development of type 1 diabetes.

ing the auto-destructive process.

However, a host of environmental

triggers, including infectious agents

n Within 5-10 years after clinical

and food antigens, may be involved

presentation, b-cell loss is complete;

in initiating the autoimmune process,

at this point, insulin deficiency is

which is initially detected by the

absolute, C-peptide secretion is lost,

presence of autoantibodies to islet

and circulating islet cell antibodies

cell components (GAD65 or GADA,

might not be detected.

ICA512 or IA-2A, zinc transporter 8 or

Diagnosis and

Classification/Pathogenesis

DIAGNOSIS AND CLASSIFICATION

iabetes is a chronic disorder that is 1) characterized by hyperglycemia;

2) associated with major abnormalities in carbohydrate, fat, and protein

metabolism; and 3) accompanied by a marked propensity to develop rela-

tively specific forms of renal, ocular, neurologic, and premature cardiovascular

diseases. Diabetes encompasses a wide clinical spectrum. The vast majority of

cases of diabetes fall into two broad etiopathogenetic categories:

n type 1 diabetes, the cause of which is an absolute deficiency of insulin

secretion

n type 2 diabetes, the cause of which is a combination of resistance to insu-

lin action and an inadequate compensatory insulin secretory response

Diabetes may also occur because of specific genetic defects and secondary to

a number of conditions, such as pregnancy, and syndromes, as well as diseases of

the pancreas, several endocrinopathies, and use of certain drugs.

Although type 1 diabetes accounts for ~5-10% of all diagnosed cases of diabe-

tes, its immediate risks and stringent acute treatment requirements demand rapid

recognition, early diagnosis, and effective management. This chapter explores char-

acteristics that differentiate type 1 diabetes from other forms of diabetes, discusses

criteria for correct diagnosis, and illustrates various clinical presentations.

CRITERIA FOR DIAGNOSIS

The criteria for diagnosing diabetes is a fasting plasma glucose concentration

≥126 mg/dL (7.0 mmol/L), a random plasma glucose level ≥200 mg/dL (11.1

mmol/L) and/or A1C ≥6.5% in the presence of the signs and/or symptoms of

diabetes. If the signs and/or symptoms are absent, plasma glucose concentrations

must be repeated on more than one occasion to diagnose diabetes. An oral glucose

tolerance test (OGTT) is rarely needed, and its use is contraindicated (Table 1.1)

in the face of dehydration and acidosis.

The clinical signs and/or symptoms that accompany diabetes are due to persis-

tent hyperglycemia and include polyuria, polydipsia, fatigue, polyphagia, weight

loss, and blurred vision. If there is ketosis or ketoacidosis, abdominal pain, vomit-

ing, dehydration, and altered level of consciousness can occur. In the young child

or infant, these signs or symptoms are frequently missed until the child presents

6 Medical Management of Type 1 Diabetes

Table 1.1 Criteria for Diagnosis of Diabetes in

Nonpregnant Adults

Diagnosis of diabetes in nonpregnant adults should be restricted to those who have one of

the following:

n Symptoms of diabetes plus casual plasma glucose concentration greater than or equal

to 200 mg/dL (11.1 mmol/L). The classic symptoms of diabetes include polyuria, poly-

dipsia, and unexplained weight loss. Casual refers to any time of day without regard to

time since last meal.

n Fasting plasma glucose greater than or equal to 126 mg/dL (7.0 mmol/L). Fasting is

defined as no caloric intake for at least 8 h.

n 2-h plasma glucose greater than or equal to 200 mg/dL (11.1 mmol/L) during an oral

glucose tolerance test (OGTT).* The test should be performed using a glucose load

containing the equivalent of 75 g anhydrous glucose dissolved in water.

n A1C ≥6.5%

In the absence of unequivocal hyperglycemia with acute metabolic decompensation, these

criteria should be confirmed by repeat testing on a different day.

*An OGTT is rarely needed to diagnose type 1 diabetes and is not recommended for routine clinical use.

as significantly ill due to ketoacidosis associated with dehydration, acidosis, and/

or develops a severe candidal diaper rash.

An elevated glycated hemoglobin (A1C) confirms the presence of significant

preexisting hyperglycemia (barring the presence of a hemoglobin variant). Pre-

diabetes (previously known as impaired glucose tolerance or impaired fasting glu-

cose) as distinguished from diabetes, refers to abnormal plasma glucose values that

do not meet the established criteria to diagnose diabetes. Pre-diabetes may be seen

in the development of type 1 diabetes as the result of the autoimmune destruction

of the b-cell mass, but is rarely detected clinically outside of research protocols in

which high-risk relatives undergo screening and close follow-up.

RISK OF DEVELOPING TYPE 1 DIABETES

Although type 1 diabetes is much less common in the general population than

type 2 diabetes, type 1 diabetes is by no means rare among children and young

adults. Data derived from the SEARCH study in the US showed that 0.78 per

1,000 children under the age of 10 have diabetes. Type 1 accounts for more than

80% of these cases. In youths 10-19 years of age, 2.80 per 1,000 have diabetes:

85.1% of white youths of this age-group have type 1, while the percentage is

lower among other ethnic/racial groups—53.9% in Hispanic youth, 42.2% in

non-Hispanic blacks, 30.3% in Asian/Pacific Islanders, and 13.8% in American

Indian youth.

Type 1 diabetes has been increasing 3-4% per year in youths, and even

more in young children under the age of 5 years. This makes diabetes one of the

Diagnosis and Classification/Pathogenesis

most common childhood diseases, with a much higher incidence rate than other

chronic childhood diseases, such as cystic fibrosis, juvenile rheumatoid arthritis,

nephrotic syndrome, muscular dystrophy, or leukemia. About 160,000 people

under age 20, and 400,000 people over 20 years of age, have type 1 diabetes.

The annual incidence of type 1 diabetes decreases after age 20. In those over

20 years old, incidence is similar in men and women, and it is lower in African

Americans, Hispanics, Asian Americans, and American Indians than in whites, as

is found in the younger age range.

Type 1 diabetes has strong HLA (human leukocyte antigen) associations.

There is linkage to the DQA and DQB genes, and diabetes risk is also influenced

by the DR genes. HLA-DR/DQ alleles can either be predisposing or protec-

tive, and the general population and family members can be assessed for risk

by genetic evaluation. Most whites with type 1 carry HLA-DR3 or HLA-DR4

alleles, in blacks it is HLA-DR7, and in Japanese it is HLA-DR9. The statistical

risk of a family member developing type 1 diabetes is linked to the genetic simi-

larities of the family members. For example, when one identical twin develops

diabetes, the risk to the other twin is 25-50%. This is in contrast to a 0.4% risk

in the general population, a 15% risk in HLA-identical siblings, and a 1% risk in

HLA-nonidentical siblings. Without knowing HLA type, in general, the risk for

type 1 diabetes in a first-degree family member is ~5%.

DISTINGUISHING TYPE 1 DIABETES FROM OTHER FORMS

Type 1 Diabetes

Type 1 diabetes can develop at any age. Although more cases are diagnosed

before the patient is 20 years old, it also occurs in older individuals. Because

patients with type 1 diabetes are insulinopenic, insulin therapy is essential to pre-

vent rapid and severe dehydration, catabolism, ketoacidosis, and death (Table

1.2). Patients who are diagnosed with symptoms are usually lean and have expe-

rienced significant weight loss, polyuria, polydipsia, and fatigue before presenta-

tion. Some patients are diagnosed without any or with more subtle symptoms

and they may be overweight, reflecting the secular trend of increasing obesity

amongst adults and children. At presentation, there is often significant elevation

of A1C levels, providing evidence of weeks, if not months, of hyperglycemia. In

addition, 85-90% have circulating autoantibodies directed against one or more

islet cell components (GADA, IA-2A, ZnT8A and IAA). C-peptide levels, which

fall to undetectable levels over time, may be in the low normal range at diagno-

sis. Profound insulinopenia occurs even though the pancreas from patients with

long standing type 1 diabetes shows that most retain some islet tissue (1-2%),

while others have a pattern of lobular destruction with destroyed and normal-

appearing islets.

Type 2 Diabetes

In contrast, patients with type 2 diabetes are less likely to develop ketoaci-

dosis unless severely stressed physiologically, are generally but not always obese,

8 Medical Management of Type 1 Diabetes

Table 1.2 Distinguishing Characteristics of the Major Types of

Ðiabetes

Clinical Classes

Type 1 diabetes

b-Cell destruction, usually leading to absolute insulin deficiency

Type 2 diabetes

Ranging from predominantly insulin resistance with relative insulin deficiency to pre-

dominantly an insulin secretory defect with insulin resistance

Secondary and other types of diabetes

Gestational diabetes mellitus

Distinguishing Characteristics

Type 1 diabetes patients may be of any age, are occasionally but not usually obese, and

often have abrupt onset of signs and symptoms with insulinopenia before age 20. They

often present with ketosis in conjunction with hyperglycemia and are eventually dependent

on insulin therapy to prevent ketoacidosis and to sustain life.

Type 2 diabetes patients usually are >30 years old at diagnosis, are obese, and have

relatively few classic symptoms. They are not typically prone to ketoacidosis except dur-

ing periods of stress. Although not dependent on exogenous insulin for survival, they may

require it for adequate control of hyperglycemia.

Forms of diabetes not easily classified as type 1 or type 2, such as ketosis-prone diabetes

in otherwise phenotypically type 2 individuals, or gradual-onset antibody-positive diabetes

in adults, referred to as LADA, are increasingly being recognized.

Patients with secondary and other types of diabetes have certain associated conditions or

syndromes (see Table 1.3).

Patients with gestational diabetes mellitus have onset or discovery of glucose intolerance

during pregnancy.

may be asymptomatic or only mildly symptomatic, and usually have a family his-

tory of diabetes. Type 2 diabetes is said to generally present after age 30, but an

increasing number of obese adolescents and young adults have been developing

type 2 diabetes, especially among African Americans, American Indians/Native

Alaskans, Hispanics, and Asian/Pacific Islanders. Note that some of these patients

present in ketoacidosis, or with hyperosmolar nonketotic coma, both of which

can be fatal. The discrimination between type 2 and type 1 diabetes is becoming

increasingly difficult in many cases, as patients with a type 2 phenotype may pres-

ent in ketoacidosis but later become insulin-independent. Conversely, more type

1 patients are overweight or obese at the time of presentation.

Patients with type 2 diabetes are not absolutely dependent on exogenous

insulin for survival, although insulin therapy is often used to lower blood glucose

levels, since there appears to be progressive b-cell failure in type 2 diabetes as

well (Table 1.2).

Diagnosis and Classification/Pathogenesis

Not Quite Type 1 or Type 2 Diabetes

Some patients are difficult to categorize as having type 1 or type 2 diabetes.

The routinely available laboratory tests that help differentiate between the two

types are serum C-peptide levels and measurements of autoantibodies to islet cell

components; however, even these tests can be problematic. Although almost all

patients with longstanding type 1 diabetes will have C-peptide values below the

lower limit of normal for that assay method, with most being undetectable, at

diagnosis, C-peptide may be in the normal range while there is still a viable b-cell

mass. Approximately 15% of patients with clinical type 1 diabetes do not have

autoantibodies at the time of diagnosis, and 10-15% of youth with clinical type 2

diabetes do have autoantibodies. Although not routinely used in the clinical arena,

markers of insulin resistance, such as adiponectin—which is elevated in type 1

and decreased in type 2—and lipoprotein concentrations, may help differentiate

between diabetes types.

With absent availability of measurement of autoantibodies or C-peptide, if a

patient is <20 years old, not obese, and has signs and symptoms of diabetes and an

elevated fasting plasma glucose, the physician should assume type 1 diabetes and

treat with insulin. The presence of moderate ketonuria with hyperglycemia in an

otherwise unstressed individual strongly supports a diagnosis of type 1 diabetes,

whereas the absence or modest ketonuria is of no diagnostic value.

Clinicians should also be aware that in some cases, typically adults, patients

presenting with type 2 diabetes subsequently may be discovered to have type 1

diabetes. In these individuals, autoantibodies to islet cell components may indicate

the eventual need for insulin therapy. These patients are usually lean, and their

insulin requirements increase as they develop manifestations of complete insulin

deficiency. The condition is referred to as LADA and studies suggest that genes

associated with type 1 and type 2 coexist in patients felt to have LADA.

In contrast, occasionally some adolescents and young adults who present with

typical signs and symptoms of type 1 diabetes, particularly ketosis, later require

no or only intermittent insulin treatment. This occurs mainly in African Ameri-

cans. Table 1.3 illustrates specific conditions often associated with other forms of

diabetes and glucose intolerance. Further studies are required to determine the

pathophysiology of these conditions.

Genetic Defects Presenting with Childhood Onset

Several forms of diabetes are associated with monogenetic defects in b-cell

function. These forms of diabetes are frequently characterized by onset of mild

hyperglycemia at an early age, generally before age 25. They were formerly referred

to as maturity-onset diabetes of the young (MODY), and they are characterized by

impaired insulin secretion with minimal or no defects in insulin action. They are

inherited in an autosomal-dominant pattern. Abnormalities at six genetic loci on

different chromosomes have been identified to date resulting in mutations on:

n chromosome 12, HNF-1a (hepatic nuclear factor, MODY3)

n chromosome 7p, glucokinase (MODY2)

10 Medical Management of Type 1 Diabetes

n chromosome 20q, HNF-4a gene (MODY1)

n chromosome 13, in the insulin promoter factor-1 gene (IPF-1, MODY4)

n chromosome 17, HNF-1b (MODY5)

n chromosome 2, NeuroD1 (MODY6)

Neonatal diabetes (NDM) is a monogenic form of diabetes that occurs in the

first 6 months of life. Incident rates are 1 in 100,000-500,000 live births. Low birth

weight and failure to thrive may be associated with NDM, and 50% of cases are

the permanent form of NDM (PNDM). The others are transient but diabetes can

recur later in life. The most common forms of PNDM are due to Kir6.2 (KCNJ11)

and SUR1 (sulfonylurea receptor 1) defects (ABCC8), which can be treated with

oral sulfonlyureas, as can MODY 1, 3, and 4.

Table 1.3 Other Specific Types of Diabetes

Genetic Defects of b-Cell Function

Examples: Kir6.2 (KCNJ11), SUR1 (ABCC8) (permanent neonatal diabetes, PNDM);

chromosome 12, HNF-1a (hepatic nuclear factor, MODY3); chromosome 7p, glucokinase

(MODY2); chromosome 20q, HNF-4a gene (MODY1); chromosome 13, in the insulin pro-

motor factor-1 gene (IPF-1, MODY4); chromosome 17, HNF-1b (MODY5); chromosome 2,

NeuroD1 (MODY6)

Genetic Defects in Insulin Action

Examples: type A insulin resistance, leprechaunism, Rabson-Mendenhall syndrome,

lipoatrophic diabetes

Diseases of the Exocrine Pancreas

Examples: pancreatitis, trauma or pancreatectomy, neoplasia, cystic fibrosis, hemo

chromatosis, fibrocalculous pancreatopathy

Endocrinopathies

Examples: acromegaly, Cushing’s syndrome, glucagonoma, pheochromocytoma, hyper-

thyroidism, somatostatinoma, aldosteronoma

Drug- or Chemical-Induced Diabetes

Examples: Vacor, pentamidine, nicotinic acid, glucocorticoids, diazoxide, interferon-a,

tacrolimus, second-generation antipsychotics

Infections

Examples: congenital rubella, cytomegalovirus

Uncommon Forms of Immune-Mediated Diabetes

Examples: “stiff man” syndrome, anti-insulin receptor antibodies

Genetic Syndromes Sometimes Associated with Diabetes

Examples: Down’s syndrome, Klinefelter’s syndrome, Turner’s syndrome, Wolfram’s

syndrome, Friedreich’s ataxia, Huntington’s chorea, Lawrence-Moon-Bardet-Biedl

syndrome, myotonic dystrophy, porphyria, Prader-Willi syndrome

Diagnosis and Classification/Pathogenesis

Point mutations in mitochondrial DNA have been found to be associated with

diabetes and deafness. In Wolfram Syndrome (referred to as DIDMOAD), dia-

betes and deafness are also associated with diabetes insipidus and optic atrophy.

There also are unusual causes of diabetes that result from genetically determined

abnormalities of insulin action. Leprechaunism and the Rabson-Mendenhall syn-

drome are two pediatric syndromes that have mutations in the insulin receptor

gene with subsequent alterations in insulin receptor function and extreme insulin

resistance. The former has characteristic facial features and is usually fatal in

infancy, whereas the latter is associated with abnormalities of teeth and nails and

pineal gland hyperplasia.

CLINICAL PRESENTATION OF TYPE 1 DIABETES

The presentation of type 1 diabetes covers a broad range, from mild non-

specific symptoms or no symptoms to coma. In children, establishing the cor-

rect diagnosis is often delayed because the presenting symptoms are ascribed to

another process. For example, vomiting and lethargy may be felt to be due to

gastroenteritis. Because adequate urine output continues as the result of osmotic

diuresis, the child is not considered to be dehydrated and in need of medical

care. Polyuria may be incorrectly attributed to urinary tract infection or enure-

sis; anorexia rather than polyphagia may occur; and fatigue, irritability, weight

loss, deterioration of school performance, and secondary enuresis are ascribed

to emotional problems. In some cases, “failure to thrive” may be an overlooked

indication of diabetes in a young child.

Approximately 75% of cases are diagnosed within 1 month of the onset of

symptoms; 25% of patients with previously undiagnosed type 1 diabetes present

in diabetic ketoacidosis (DKA). Delayed diagnosis continues to be a serious and

occasionally fatal problem, especially among poor and younger children. DKA

rates approach 40% in children under 3 years of age and 60% in children under

2 years at diagnosis. The symptoms of polyuria are less obvious in the young

child and are frequently missed until metabolic decompensation has occurred.

These very young children frequently present with severe dehydration, meta-

bolic acidosis, and a clinical history that is inconsistent with the severity of their

clinical appearance (e.g., absence of diarrhea or significant vomiting). Because of

the delay in the diagnosis of the younger child, the frequency of coma as a pre-

senting feature is considerably greater in children <2 years of age than in older

children, adolescents, and adults. In young adults, the presentation is often less

acute, although an absolute requirement for insulin becomes evident with time.

CONCLUSION

Patients with type 1 diabetes are dependent on insulin for as long as they live.

Any lean individual <20 years of age with typical signs and symptoms of hyper-

glycemia accompanied by weight loss should be assumed to have type 1 diabetes.

A high index of suspicion is needed to diagnose diabetes in very young children

or elderly patients.

12 Medical Management of Type 1 Diabetes

BIBLIOGRAPHY

American Diabetes Association: Care of children and adolescents with

type 1 diabetes mellitus (Position Statement). Diabetes Care 28:

186-212, 2005

The DIAMOND Project Group: Incidence and trends of childhood type 1 dia-

betes worldwide 1990-1999. Diabet Med 23:857-866, 2006

Expert Committee on the Diagnosis and Classification of Diabetes Mellitus:

Report of the Expert Committee on the Diagnosis and Classification of

Diabetes Mellitus. Diabetes Care 26 (Suppl. 1):S5-S20, 2003

Lindstrom T, Frystykt J, Hedman CA, Flyvbjerg A, Arnqvist HJ: Elevated cir-

culating adiponectin in type 1 diabetes is associated with long diabetes dura-

tion. Clin Endocrinol 65:776-782, 2006

Michels AW, et al.: Immune intervention in type 1 diabetes. Seminars in

Immunology 23:214-219, 2011

The National Diabetes Information Clearinghouse: Monogenic Forms of

Diabetes: Neonatal Diabetes Mellitus and Maturity-onset Diabetes of the

Young. www.diabetes.niddk.nih.gov/dm/pubs/mody

Rewers A, et al.: Presence of diabetic ketoacidosis at diagnosis of diabetes mellitus

in youth: the SEARCH for Diabetes in Youth Study, Pediatrics 2007-1105

Rosenbloom AL, Silverstein JK: Type 2 Diabetes in Children and Adolescents.

Alexandria, VA, American Diabetes Association, 2003

SEARCH for Diabetes in Youth Study Group: The burden of diabetes mellitus

among U.S. youth: prevalence estimates from the SEARCH for Diabetes in

Youth Study. Pediatrics 118:1510-1518, 2006

Vaziri-Sani F.: A novel triple mix radiobinding assay for the three ZnT8

(ƵnT8-RWQ) autoantibody variants in children with newly diagnosed dia-

betes. J Immun Methods 371:25-37, 2011

Diagnosis and Classification/Pathogenesis

PATHOGENESIS

he primary defect in type 1 diabetes is decreased insulin secretion by

pancreatic b-cells. This single defect accounts for the hyperglycemia,

polyuria, polydipsia, weight loss, dehydration, electrolyte disturbance,

and ketoacidosis observed in patients presenting for the first time with type 1

diabetes. The capacity of normal pancreatic b-cells to secrete insulin is far in

excess of that normally needed to control carbohydrate, fat, and protein metabo-

lism. As a result, clinical onset is preceded by an extensive asymptomatic period

during which b-cells are inexorably destroyed. The evolving process of b-cell

destruction reaches a point where insufficient insulin is secreted to maintain

normal plasma glucose concentrations, which causes the broadly predictable

abnormalities in carbohydrate, fat, and protein metabolism characterizing the

uncontrolled diabetic condition.

Most patients with type 1 diabetes have immune-mediated diabetes. This form

of diabetes results from a cellular-mediated autoimmune destruction of the b-cells

of the pancreas. Most of the discussion in this section deals with this form of type

1 diabetes—immune-mediated diabetes. However, some forms of type 1 diabetes

have no evidence of autoimmunity or other known etiology and are labeled “idio-

pathic.” Some of these patients have permanent insulinopenia and are prone to

ketoacidosis. Although only a minority of patients with type 1 diabetes fall into the

idiopathic category, of those who do, most are of African or Asian origin. Individ-

uals with this form of diabetes often suffer from episodic ketoacidosis and exhibit

varying degrees of insulin deficiency between episodes. This form of diabetes is

strongly inherited, lacks immunological evidence for b-cell autoimmunity, and is

not HLA associated. A requirement for insulin replacement therapy in affected

patients may come and go.

PATHOPHYSIOLOGY OF THE CLINICAL ONSET

OF TYPE 1 DIABETES

Insulin is the primary hormone that suppresses hepatic glucose production,

lipolysis, and proteolysis. It increases the transport of glucose into adipocytes

and myocytes and stimulates glycogen synthesis. In the presence of adequate

plasma amino acids, insulin maintains or perhaps stimulates whole-body protein

anabolism. As such, insulin is the primary hormone of anabolism of meal-derived

nutrients (Table 1.4).

In the postabsorptive state, the plasma concentration of glucose is maintained

in a narrow range (80-95 mg/dL [4.4-5.3 mmol/L]) by precise regulation of

hepatic glucose release and peripheral glucose utilization.

Basal plasma insulin concentrations maintain hepatic glucose release at a rate

of 1.9-2.1 mg/kg/min (10-12 µmol/l/kg/min). This is of critical importance to

provide adequate glucose for the brain, which accounts for nearly 50% of total

glucose utilization under these conditions. With prolonged fasting, the plasma

insulin concentration decreases even further, permitting increased mobilization

of free fatty acids (FFAs). The resulting increase in circulating FFA concentra-

tion drives hepatic ketogenesis, which results in ketosis. Increased availability of

plasma FFAs, b-hydroxybutyrate, and acetoacetate provides alternative metabolic

14 Medical Management of Type 1 Diabetes

Table 1.4 Physiological Effects of High- Versus Low-Insulin States

High-Insulin (Fed) State

Low-Insulin (Fasted) State

Liver

Glucose uptake

Glucose production

Glycogen synthesis

Glycogenolysis

Lipogenesis

Absent lipogenesis

Absent ketogenesis

Ketogenesis

Absent gluconeogenesis

Gluconeogenesis

Muscle

Glucose uptake

Absent glucose uptake

Glucose oxidation

Fatty acid, ketone oxidation

Glycogen synthesis

Glycogenolysis

Sustained protein synthesis

Proteolysis and amino acid release

Adipose tissue

Glucose uptake

Absent glucose uptake

Lipid synthesis

Lipolysis and fatty acid release

Triglyceride uptake

Absent triglyceride uptake

fuels to glucose and reduces the rates of glucose utilization by peripheral tissues

and brain.

After ingestion of a mixed meal, nearly 85% of ingested glucose enters the

systemic circulation. The increasing arterial glucose concentration stimulates

the secretion of insulin into the portal vein. About half of the secreted insulin is

extracted by the liver, which signals the suppression of hepatic glucose release.

The unextracted insulin enters the systemic circulation, where it stimulates glu-

cose uptake, primarily by muscle, and decreases lipolysis and proteolysis. This

facilitates a continuous entry of glucose into the systemic circulation by permit-

ting a switch from endogenous glucose production to exogenous glucose. As

dietary glucose entry decreases with the absorption of the meal-derived carbohy-

drate, plasma glucose decreases, as does the secretion and plasma concentration

of insulin. When plasma glucose reaches or even falls slightly below basal con-

centrations, hepatic glucose production is again increased by both the decrease

in plasma insulin and an increase in plasma glucagon concentration (Table 1.4).

Amylin, a glucoregulatory hormone, is produced in the pancreatic b-cell

and co-secreted with insulin. Amylin regulates postprandial glucose concentra-

tions by slowing gastric emptying, suppressing postprandial glucagon secretion,

and reducing food intake. Amylin complements the effects of insulin, and both

act together to regulate postmeal glucose concentrations. Type 1 diabetes is an

amylin-deficient state.

PROGRESSION OF METABOLIC ABNORMALITIES

DURING ONSET

The insulin secretory reserves of the normal pancreas are considerable.

Therefore, individuals destined to develop type 1 diabetes go through a variable

interval of months to years of autoimmune b-cell destruction before abnormali-

ties in insulin secretion or glucose metabolism can be detected (Fig. 1.1). During

this time period, amylin secretion is also diminished and then lost.

The earliest detectable abnormality in insulin secretion is a progressive reduc-

tion of the immediate (first-phase) plasma insulin response during intravenous

Diagnosis and Classification/Pathogenesis

Figure 1.1 Proposed scheme of natural history of type 1 diabetes. Timing

of trigger in relation to immunologic abnormalities is unknown. Note that

overt diabetes is not apparent until insulin secretory reserves are <10-20%

of normal.

glucose tolerance testing. This impairment alone has little deleterious effect

on overall glucose homeostasis: fasting plasma glucose concentrations remain

normal, and the response to an OGTT is virtually unimpaired. At this stage

of the disease, most affected individuals have circulating autoantibodies to islet

cell components, islet cell antibodies (ICAs), including antibodies to their own

insulin (IAA) and to other islet cell antigens (e.g., glutamic acid decarboxylase

[GADA], islet tyrosine phosphatases [IA-2A], and zinc transporter 8 [ZnT8A]).

These are markers of an ongoing autoimmune process that eventuates in type 1

diabetes. There is variability to the autoantibody pattern, in the years prior to

diagnosis, IA-2A titers increase, but then decrease after diagnosis, while GADA

titers persist. Insulin autoantibodies, IAA, are more prevalent in young children.

The presence and then persistence of two or more autoantibodies is highly pre-

dictive and has replaced assessment of first-phase insulin secretion to determine

risk of developing type 1 diabetes (Fig. 1.1). Greater than 70% of those who

have 2 or more autoantibodies will develop diabetes over a 7 year observation

period.

CLINICAL ONSET OF DIABETIC SYMPTOMS

AND METABOLIC DECOMPENSATION

When ongoing destruction has reduced b-cell mass by 80-90%, the individ-

ual’s insulin secretory capacity becomes insufficient to normally regulate hepatic

glucose production (Fig. 1.1). Initially, only postprandial hyperglycemia occurs,

reflecting a failure to adequately suppress hepatic glucose production during meal

absorption together with some decrease in peripheral glucose utilization. This

may also be exacerbated by amylin deficiency. As insulin secretion is further com-

promised, progressive fasting hyperglycemia occurs as a result of increased basal

hepatic glucose production and decreased glucose uptake by peripheral tissue.

16 Medical Management of Type 1 Diabetes

Hyperglycemia per se may further compromise glucose utilization by reducing

the number and/or activity of glucose transporters available on both insulin-

dependent and non-insulin-dependent tissues, a phenomenon known as “glucose

toxicity.”

When the plasma glucose concentration exceeds the renal threshold of ~180

mg/dL (10.0 mmol/L), glucosuria results in an osmotic diuresis, generating the

classic symptoms of polyuria and a compensatory polydipsia. If untreated, the

symptoms usually progress as the hyperglycemia and glucosuria increase. With

evolving insulin deficiency, weight loss occurs as body fat and protein stores are

reduced because of increased rates of lipolysis and proteolysis, and calories are

lost in the urine. With the superimposed metabolic abnormalities of diabetes

itself or with a minor viral or bacterial infection, plasma concentrations of glu-

cagon, growth hormone, epinephrine, and cortisol increase. These hormones

antagonize insulin’s effect, further promoting hepatic glucose production (by

stimulating both glycogenolysis and gluconeogenesis), lipolysis, ketogenesis, and

proteolysis. As long as fluid intake is sufficient to offset the fluid losses resulting

from the combined diuresis of both glucosuria and ketonuria, some individu-

als can remain compensated for weeks, if not months. Should the individual be

unable to consume adequate amounts of fluid as a result of nausea from the keto-

sis or because of an intercurrent illness, rapid and severe losses of both intra- and

extracellular fluid and electrolytes can ensue and, in the course of hours, lead to a

clinical presentation of severe ketoacidosis.

Remission or Honeymoon Phase

At initial presentation with symptomatic hyperglycemia and/or ketosis, circu-

lating insulin concentrations are low, and there is no significant b-cell response to

any of the usual insulin secretagogues. Initially, exogenous insulin requirements

are relatively large, due not only to the reduced insulin secretion but also to insu-

lin resistance and counterregulatory hormone elevation.

After the correction of the hyperglycemia, metabolic acidosis, and ketosis,

endogenous insulin secretion improves from the residual, albeit small, b-cell pop-

ulation (Fig. 1.1). During this time, exogenous insulin requirements may decrease

dramatically. During the remission or honeymoon period, which may last for up

to 1 year or longer, good metabolic control may be easily achieved with either

conventional or intensive insulin therapy. The need for increasing exogenous

insulin replacement is inevitable and should always be anticipated. Evidence from

the Diabetes Control and Complications Trial follow-up cohort suggests that

intensive insulin therapy from early diagnosis prolongs C-peptide secretion and

thus creates less major hypoglycemia and less microvascular complications 10

years after diagnosis. As a result, intensive insulin therapy with strict attention

to diet and self-monitoring of blood glucose should be initiated at diagnosis and

maintained. Having DKA at presentation of diabetes adversely affects the remis-

sion phase duration.

Finally, within 5 years for children and 10 years after clinical presentation

regardless of age at presentation, b-cell destruction is essentially complete. At this

point, insulin deficiency is usually absolute.

Diagnosis and Classification/Pathogenesis

Attempts to Preserve the b-Cell Mass

A number of therapies have been and are being tested to prevent the total

destruction of the b-cell mass, both prior to and after the diagnosis of type 1

diabetes. The outcome measure is the C-peptide response to a standardized

mixed meal tolerance test. These trials can be divided into those that are immune

suppressive, those that are attempting immunoregulation, and those involving

intense metabolic control. Early therapeutic attempts centered mainly on gen-

eral immune suppression. Although effective in small pilot studies in prolong-

ing the honeymoon period or delaying the onset of overt type 1 diabetes, none

resulted in permanent remission. Two large, multicenter intervention trials

involving either low-dose parenteral insulin therapy (Diabetes Prevention Trial 1

[DPT-1]) or nicotinamide (ENDIT Trial) as immunoregulatory agents in the

pre-type 1 diabetes state showed no benefit in delaying or preventing the onset

of type 1 diabetes. A second arm of the DPT-1 using oral insulin in those deemed

to be of moderate risk (25-50% risk) of developing diabetes showed that a subset

of subjects with insulin autoantibodies had a several-year delay in progression to

diabetes, and this is being evaluated now in the multinational TrialNet consortia

that was developed after DPT-1. Other prevention studies have looked at envi-

ronmental therapies such as using supplemental vitamin D, omega fatty acids, or

altering complex dietary protein exposure using hydrolyzed formula compared

to cow’s milk.

TrialNet has completed studies on a number of agents at the diagnosis of

type 1 diabetes, including mycophenalate mofetil (an inhibitor of purine syn-

thesis) plus daclizumab (anti-CD25), which showed no benefit, and rituximab

(an anti-b-cell antibody), and abatacept (CTLA-4 Ig, T-cell costimulation

modulation), which both showed an attenuation in loss of C-peptide over the

first year of disease due to an initial response followed by a decline in c-peptide

that mirrored the control group. Studies of anti-CD3 monoclonal antibodies

at onset of type 1 have found some preservation of C-peptide for at least 1

year, but may be associated with acute cytokine release and transient activa-

tion of Epstein-Barr virus infection. Ongoing larger studies are still underway

to determine the duration of therapeutic effect and safety. Additional inter-

ventions being evaluated include GAD-Alum, anti-thymocyte globulin, BCG,

insulin peptide B:9-23, heat shock protein DiaPep277, α-1 antitrypsin, closed-

loop insulin delivery, and others.

These intervention trials offer an opportunity to preserve a significant mass

of b-cells and potentially prevent or delay overt diabetes and modify its course.

Potential therapeutic modalities must be approached with caution and should be

utilized only in conjunction with carefully defined scientific studies. Individuals

at risk for diabetes because of family history and those newly diagnosed should be

informed about available clinical trials designed to attempt to interdict the type

1 process.

GENETICS AND IMMUNOLOGY OF TYPE 1 DIABETES

Type 1 diabetes is a genetically influenced and immunologically mediated

disease with a prolonged asymptomatic phase (pre-type 1 diabetes), which

18 Medical Management of Type 1 Diabetes

Table 1.5 Approximate Familial Risk of Type 1 Diabetes

Relationship to Proband

Risk (%)

Sibling

5-10

Identical twin

25-50

HLA

Identical

Haploidentical

Nonidentical

Father

Mother

Offspring of father

Offspring of mother

General population

0.3-0.4

Modified from Muir A, Schatz DA, Maclaren NK: The pathogenesis, prediction, and prevention of

insulin-dependent diabetes mellitus. Endocrin Metab Clin North Am 21:199-219, 1992.

eventually results in progressive b-cell destruction, insulin deficiency, and overt

clinical symptoms. The identity of the initiating event(s) remains speculative.

Viruses, food antigens, and intestinal microbes have been proposed as environ-

mental triggers of b-cell autoimmunity.

The familial predisposition to type 1 diabetes has long been known. A specific

mode of genetic transmission has not been established. Predisposition to type 1

diabetes is inherited as a heterogeneous multigenic trait with low penetrance and

gender biases. There is a higher concordance rate for type 1 diabetes in monozy-

gotic twins (25-50%) than in dizygotic twins (6%). The empirical risk of type 1

diabetes is increased in first-degree relatives of probands with the disease (Table

1.5). There is an even greater risk for offspring of fathers with diabetes who were

diagnosed at a young age; however, the age of onset of diabetes in the mother

does not seem to affect the risk for her children.

About 40-50% of the genetic predisposition to type 1 diabetes is conferred by

genes on the short arm of chromosome 6, either within or in close proximity to the

Class II HLA region of the major histocompatibility complex (MHC). At least 11

other loci have been suggested to be involved, with the largest contribution (about

10% of the genetic predisposition) being accounted for by the flanking region of

the insulin gene on chromosome 11, INS-VNTR. Shorter forms of a variable

number tandem repeated in the insulin promoter are associated with susceptibil-

ity, while longer forms are associated with protection. Other genes associated with

T-cell activation and regulation have been identified; cytotoxic T lymphocyte anti-

gen-4 (CTLA-4) and protein tyrosine phosphatase N22 (PTPN22) and multiple

genes in the interleukin (IL-2) and IL-2 receptor (IL-2R) pathways. HLA, CTLA-4,

and PTPN22 are associated with other autoimmune diseases.

The Class II MHC DR and DQ molecules are comprised of an a- and a

b-chain, which present processed antigens to T-cells. The relationship between

type 1 diabetes and specific MHC Class II region alleles is complex. There is

a strong positive relationship with HLA-DR3 and -DR4 and a strong negative

Diagnosis and Classification/Pathogenesis

Figure 1.2 Development

of auto-islet autoantibodies

among DR3/4-DQ8 siblings

of patients with type 1 dia-

betes in the DAISY (Diabetes

Autoimmunity Study in the

Young) study with extreme

risk for those sharing two

HLA major histocompatibility

complex (MHC) haplotypes

with sibling proband. Figure

was adapted from Aly T et al.:

Extreme genetic risk for

type 1A diabetes. PNAS

103:14074-14079, 2006.

relationship with -DR2. Indeed, more than 90% of whites with type 1 diabetes are

HLA-DR3 and/or -DR4, while 30% of children who develop type 1 are hetero-

zygote DR3/DR4. Within families, the risk for diabetes is highest for those who

are DR3/DR4 heterozygotes and who have inherited identical HLA haplotypes as

their sibling with diabetes (Fig. 1.2). There is an even stronger relationship of type

1 diabetes when DQ loci (DQa and DQb) are considered together with DR loci,

i.e., the predisposition to type 1 diabetes in whites is associated with HLA-DR3,

DQB1*0201, and with HLA-DR4, DQB1*0302, with the strongest association

being the DQa-DQb combination DQA1*0501-DQB1*0302. Other DQ alleles

appear to confer protection from type 1 diabetes, e.g., DQA1*0201-DQB1*0602

provides protection even in the presence of DQ susceptibility alleles. This suggests

that protection is dominant over susceptibility. Because Class II MHC genes regu-

late the immune response, the susceptibility and protective alleles could be involved

differentially in antigen presentation of peptides that establish and maintain toler-

ance or influence the immune response.

Autoantibodies and Autoantigens

The identification of circulating autoantibodies to islet cell components in

those who have developed diabetes and subsequently in nondiabetic first-degree

relatives has made it possible to detect the preclinical disease. Numerous circu-

lating autoantibodies have been identified, including cytoplasmic ICAs detected

by immunofluorescence, insulin autoantibodies (IAAs), auto-antibodies directed

against the enzyme GAD (GADA), autoantibodies against islet tyrosine phospha-

tase (IA-2A and IA2b), zinc transporter 8 A (ZnT8A) and several others. Most

(>90%) newly diagnosed patients with type 1 diabetes have one or another of

these circulating antibodies as do 3.5-4% of unaffected first-degree relatives.

This latter group of antibody-positive individuals is at increased risk for develop-

ing type 1 diabetes. The presence of two or more antibodies is highly predictive

of increased risk of type 1 diabetes within 5 years.

20 Medical Management of Type 1 Diabetes

These autoantibodies generally are not thought to mediate b-cell destruction

by humoral mechanisms. Rather, it is likely that as b-cells are destroyed, mul-

tiple antigens are exposed to the immune system, with generation of antibodies

directed against these components. Thus, these autoantibodies are markers of

immune activity or of b-cell damage and herald the disease process several years

before overt clinical hyperglycemia. As b-cell function is lost and “total” diabetes

evolves, ZnT8A, and IA-2 autoantibodies tend to decrease in titer and/or disap-

pear, while GADA tends to persist.

Many patients with type 1 diabetes have nonpancreatic organ-specific auto

antibodies (e.g., toward thyroid, gastric parietal cells, and, less often, adrenal

cells). Hashimoto’s thyroiditis is the most common autoimmune disorder associ-

ated with type 1 diabetes. Celiac disease is also relatively common and associated

with expression of autoantibodies to endomysium and tissue transglutaminase.

The range of organ involvement with autoimmune disorders varies from none to

severe polyglandular failure.

Screening and Intervention Trials

Humoral autoantibodies allow for the identification of individuals who are at

high risk for developing type 1 diabetes, such as those with prior transient hyper-

glycemia, and they play a role in experimental therapeutic trials directed at the

preservation of islet cell function. Screening for immunologic markers of type 1

diabetes in any population outside the context of defined research studies is dis-

couraged. Screening of high-risk individuals (e.g., first-degree relatives of someone

with type 1 diabetes) should be encouraged, provided that individuals who screen

positive are referred to centers participating in cooperative intervention studies or

other scientific investigations using appropriate techniques. All subjects who are

screened but do not enter a study should be counseled about their risk of develop-

ing diabetes, and follow-up should be offered.

Cell-Mediated Immunologic Dysfunction

The existence of insulitis (lymphocytic infiltration of the pancreas by mono-

nuclear cells) has been known for decades and was the earliest evidence for the

autoimmune nature of type 1 diabetes. There is evidence of a role for both T- and

b-cells as well as lymphokines in the pathophysiology of the b-cell destruction in

both human and animal models. However, type 1 diabetes in most animal models

is considered a cell-mediated disease because adoptive transfer occurs with T-cells

but not with autoantibody transfer. Although therapies directed against T-cells

might be more successful, strategies to deplete b-cells and/or autoantibodies

might have a role in preventing diabetes.

Environmental Triggers

The concordance rate of diabetes of identical twins suggests that environmen-

tal factors may be important in the pathogenesis of type 1 diabetes. Viral infec-

tions, e.g., enteroviruses such as Coxsackie B4, rotavirus, and congenital rubella,

have been inconsistently implicated as triggers for the immunologic process. The

Diagnosis and Classification/Pathogenesis

gut microflora play a pathophysiological role through a variety of potential mech-

anisms including a chronic low-grade inflammation and altered intestinal barrier

function. Exposure to substances toxic to the b-cells accounts for only a very small

number of cases. Prolonged breast-feeding is reported to lower the incidence rates

for type 1 diabetes. Highly hydrolyzed milk formula may decrease β-cell autoim-

munity to an even greater extent than cow’s milk due to the adverse effect of early

exposure to complex dietary proteins. Early gluten exposure has been implicated

since a gluten-free diet dramatically decreases type 1 diabetes in animal models.

Little direct evidence exists to link any specific factor(s) to triggering autoimmune

destruction of the b-cells in type 1 diabetes in humans.

CONCLUSION

Individuals who are genetically or otherwise predisposed to develop type 1

diabetes eventually demonstrate near total failure of insulin secretion as the result

of an immunologically mediated progressive destruction of b-cell mass. The

emergence of insulinopenia is associated with several intracellular abnormalities

in both liver and muscle tissue, leading to excessive hepatic glucose production,

decreased muscle glucose uptake, frank glucose intolerance, and, if untreated,

ketoacidosis. Because insulin deficiency is primary, patients are dependent on

exogenous insulin for life.

BIBLIOGRAPHY

Aly et al.: Extreme genetic risk for type 1A diabetes. Proc Natl Acad Sci U S A

103:14074-14079, 2006

American Diabetes Association: Prevention of type 1 diabetes mellitus (Position

Statement). Diabetes Care 26 (Suppl. 1):S140, 2003

American Diabetes Association: Report of the Expert Committee on the

Ðiagnosis and Classification of Diabetes Mellitus. Diabetes Care 26

(Suppl. 1):S5-S20, 2003

Atkinson MA, Maclaren NK: The pathogenesis of insulin-dependent diabetes

mellitus. N Engl J Med 331:1428-1436, 1994

Bach JF: Insulin-dependent diabetes mellitus as an autoimmune disease. Endocr

Rev 15:516-542, 1994

Eisenbarth G: Update in type 1 diabetes. JCEM 92:2403-2407, 2007

Genuth SM: Diabetic ketoacidosis and hyperglycemic hyperosmolar coma. Curr

Ther Endocrinol Metab 6:438-447, 1997

Harjutsalo V, Reunanen A, Tuomilehto J: Differential transmission of type

1 diabetes from diabetic fathers and mothers to their offspring. Diabetes

55:1517-1524, 2006

Knip M et al.: Dietary intervention in infancy and later signs of beta-cell

autoimmunity. N Engl J Med 363:1900-1908, 2010

22 Medical Management of Type 1 Diabetes

Long SA.: Defects in Il-2R signaling contribute to diminished maintenance of

FOXP3 expression in CD4(+) CD25(+) regulatory T-cells of type 1 diabetic

subjects. Diabetes 59:407-415, 2010

Nepom GT: Immunogenetics and IDDM. Diabetes Reviews 1:93-103, 1993

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Skyler JS, Marks JB: Immune intervention in type I diabetes mellitus. Diabetes

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Highlights

Diabetes Standards

and Education

PHILOSOPHY AND GOALS

demonstrated a link between poor

glycemic control and development

n The main influencers of what

of diabetic complications. The Epi-

treatment regimen a patient will

demiology of Diabetes Interventions

adopt and likelihood of achieving

and Complications (EDIC) Trial con-

treatment goals are

firmed the importance of the establish-

ment of optimal glycemic control as

• the diabetes management team’s

early as possible.

ability to assess the optimal, indi-

vidualized regimen for patient/

n The physician and patient must

family

set treatment goals together with the

• the patient’s self-care attitudes and

diabetes management team and fam-

abilities

ily. Glycemic goals should be set as

• diabetes team-patient/family align-

close to optimal as possible given the

ment of goals and ability to work

patient’s abilities and presence of risk

collaboratively

factors.

n The primary goals of treatment

n Initial and long-term clinical

are to

goals are presented in Clinical Goals.

• achieve optimal glycemic goals

They focus on

with a flexible, individualized

• metabolic stabilization

diabetes management plan

• restoration and maintenance of

• avoid severe hypoglycemia, symp-

desirable body weight

tomatic hyperglycemia, and keto-

• elimination of hyperglycemic

acidosis

symptoms and minimization of

• avoid long term microcirculatory

severe hypoglycemia

and macrovascular complications

• promote and maintain day-to-day

clinical and psychological well-

PATIENT SELF-

being

MANAGEMENT EDUCATION

• promote normal growth and

n The goal of diabetes self-

development in children

management education is to provide

patients with the knowledge, skills,

n Results from the Diabetes Control

and motivation to incorporate dia-

and Complications Trial (DCCT)

betes self-management in their daily

lives and to engage in active collabo-

n Newly diagnosed patients with

ration with the health care team. The

type 1 diabetes need to learn the

process includes:

basic skills that will enable them to

implement their treatment regimen at

• teaching of information needed for

home. Initial education should focus

diabetes self-management

on teaching survival skills, with more

• training in skills needed for treat-

in-depth information and additional

ment procedures

topics added after the patient has had

• guidance and empowerment of the

time to adjust to diabetes self-care.

patient, incorporating his or her

Written patient guidelines for detect-

experiences and preferences, in

ing and treating hypoglycemia and

devising methods to fit the treat-

for managing mild illnesses reinforce

ment regimen into the individual’s

self-management skills that are not

lifestyle

routinely needed and should be part

• counseling on reconciling diabetes

of survival skills education.

care and the individual’s view of

quality of life through the iden-

n Patient education is essential

tification of strategies needed for

for management of type 1 diabetes.

behavior change

Therefore, physicians who treat

type 1 diabetes patients need to

n Diabetes self-management educa-

provide diabetes self-management

tion is a planned process that includes

training opportunities for these

patients. Physicians can incorporate

• assessment to identify the patient’s

diabetes patient education in their

individual education needs

clinical practice by

• planning specific education

• hiring diabetes educators

strategies

• developing a team relationship

• implementation and documen

with diabetes educators working in

tation of education

the community

• evaluation of learning

• referring patients to diabetes edu-

• reassessment(s) for new needs over

cation programs recognized by the

time and across the life span

American Diabetes Association as

To be effective, diabetes self-

meeting the National Standards

management patient education must

for Diabetes Self-Management

be individualized, should be provided

Education

in the context of a team approach to

• becoming knowledgeable about

diabetes care, and needs to continue

other diabetes education resources

across the life span of the individual

in their communities

with diabetes. When indicated,

family members and caregivers will

be included.

Diabetes Standards

and Education

PHILOSOPHY AND GOALS

ype 1 diabetes is a chronic disease in which the goal of treatment has

been well defined—to achieve the best glycemic control that is possible

with the least associated risk of hypoglycemia. The diabetes management

team must work with the patient to determine which treatment strategies will

best achieve the desired outcomes. The diabetes management team comprises

a consortium that includes the endocrinologist or diabetes specialist, nurse,

dietitian, social worker, mental health professional, pharmacist, and other health

care specialists. The diabetes management team interfaces with the primary care

provider, who helps coordinate care and establishes the patient’s medical home.

Three factors that strongly influence treatment are

n the diabetes management team’s ability to assess the optimal, individual-

ized regimen for patient/family

n the patient/family’s self-care attitudes and abilities

n diabetes team-patient/family alignment of goals and ability to work col-

laboratively

The primary goals of treatment are 1) to promote and maintain day-to-day

clinical and psychological well-being; 2) to avoid severe hypoglycemia, symptom-

atic hyperglycemia, and ketoacidosis; 3) to avoid long-term microcirculatory and

macrovascular complications, and 4) to promote normal growth and development

in children. The secondary goal of treatment is patient empowerment and the suc-

cessful facilitation of the necessary behavior change to achieve the best possible

glycemic control to prevent, delay, or arrest long-term diabetes complications while

minimizing hypoglycemia and excess weight gain or disordered eating. The primary

goals are clearly achievable at variable degrees of cost, inconvenience, and risk; the

secondary goal, although more difficult, should be attainable by most patients.

GLYCEMIC CONTROL AND COMPLICATIONS:

A SUMMARY OF EVIDENCE

Evidence relating hyperglycemia and/or other metabolic consequences of

insulin deficiency to the development of vascular complications comes from

animal studies, older epidemiologic studies of European and North American

patients with type 1 diabetes, and from more recent controlled clinical trials from

Scandinavia and North America.

28 Medical Management of Type 1 Diabetes

Animal Studies

Strong experimental support for an association between metabolic abnormali-

ties and vascular complications is found in animal studies. Animals that are rendered

insulin deficient and hyperglycemic develop pathologic changes resembling early

human retinopathy, nephropathy, and neuropathy. These changes can be prevented

or ameliorated and, in some instances, reversed by early intensive insulin treatment,

by curing diabetes via pancreas or islet transplantation, or by transplanting the

affected organ into a nondiabetic animal.

Other Causes of Diabetes

Microvascular disease also develops in some patients with diabetes resulting

from removal or destruction of the islets caused by pancreatectomy, chronic pan-

creatitis, or toxicity (e.g., from the rodenticide Vacor). These observations further

support the theory that loss of insulin secretion or some consequent metabolic

derangement is responsible for microvascular abnormalities in patients with

immune-mediated type 1 diabetes. Genetic predisposition may influence the

development of microvascular, neuropathic, and other complications; however,

hyperglycemia is a prerequisite to development of these complications.

Kidney Transplantation Observations

Normal kidneys transplanted into recipients with type 1 diabetes begin to show

pathologic changes resembling diabetic nephropathy after several years. Normal

kidneys transplanted into patients with successful whole-pancreas transplantation

have less glomerulopathy than kidneys transplanted into patients treated with con-

ventional therapy. These observations point to a causative role for the diabetic

metabolic milieu.

DYSGLYCEMIA AND COMPLICATIONS FROM

POPULATION-BASED DATA

In data from 1,066 individuals aged >40 years from the 2005-2006 National

Health and Nutrition Examination Survey, the relationship between fasting

plasma glucose (FPG), A1C, and retinopathy have shown that retinal lesions do

not develop before there is an elevation of measures of glycemia. This data on a

specific and early clinical complication of diabetes points to the causative role of

even minimal hyperglycemia.

Epidemiologic Studies

Several epidemiologic studies in patients with type 1 diabetes suggest that the

higher the glucose level, the greater the incidence of microvascular disease.

Prospective Clinical Trials

The Diabetes Control and Complications Trial (DCCT) examined whether

intensive treatment with the goal of maintaining glucose concentrations close to the

Diabetes Standards and Education

normal range could decrease the frequency and severity of diabetes complications.

Investigators studied 1,441 patients with type 1 diabetes—726 with no retinopa-

thy and 715 with mild retinopathy at baseline. Patients were randomly assigned to

intensive therapy administered with insulin pumps or multiple injections of insulin

guided by blood glucose monitoring or to conventional therapy with one or two

insulin injections per day. The patients were followed a mean of 6.5 years. Results

showed that in the primary intervention cohort, intensive therapy reduced the

mean risk of developing retinopathy by 76%. In the secondary intervention group,

intensive therapy slowed the progression of retinopathy by 54% and reduced the

development of proliferative retinopathy by 47%. In both groups combined, inten-

sive therapy reduced the occurrence of microalbuminuria (>40 mg/24 h) by 39%

and albuminuria (>300 mg/24 h) by 54%. Clinical neuropathy was reduced by

60%. The most important adverse effect was a threefold increase in severe hypo-

glycemia. Comparable results were seen in the Stockholm Diabetes Intervention

Study after 5 and 8 years.

After completion of the DCCT, most of the participants were enrolled in

a long-term observational study titled the Epidemiology of Diabetes Interven-

tions and Complications (EDIC) study. The difference in the median A1C val-

ues between the conventional therapy and intensive therapy groups during the

6.5 years of the DCCT (average of 9.1% and 7.2%, respectively) narrowed dur-

ing follow-up (median at 4 years of 8.2% and 7.9%, respectively). Despite this

small difference in glycemic control between the two groups at 4 years of follow-

up, the reduction in the risk of progressive retinopathy and nephropathy that

resulted from intensive therapy persisted in EDIC study. EDIC study results at

6 years of follow-up of these two groups showed a significant difference in the

progression of the carotid intima-media thickness, a measure of atherosclerosis.

From DCCT through EDIC, and after an average of 17 years of follow-up, the

number of CVD events in the conventional group was more than double that of

intensive-therapy subjects and intensive therapy reduced the risk of any CVD

event by 42% and the risk of nonfatal myocardial infarction (MI), stroke, or

death by 57%. However, the effect of group assignment was not as significant

when comparing the original adolescent versus adult DCCT cohorts. At EDIC

year 10, it was the mean A1C level during the DCCT that accounted for 79%

of the observed difference between adults and adolescents rather than original

treatment assignment.

Data available from DCCT and from the observational study of type 1

patients from Allegheny County, Pennsylvania (Pittsburgh Epidemiology

of Diabetes Complications Experience (EDC)), conducted from 1983-2005

have shown the diabetes complication rates 30 years after the diagnosis. In the

DCCT conventional treatment group, cumulative incidence rates of prolifera-

tive retinopathy, nephropathy, and cardiovascular disease were 50%, 25%, and

14%, respectively. They were 47%, 17%, and 14%, respectively, in the EDC

cohort and 21%, 9%, and 9%, respectively, in the DCCT intensive therapy

group; in addition, less than 1% became blind, required kidney replacement

therapy, or had an amputation.

These follow-up findings strongly support the implementation of intensive

therapy and lowering of A1C as early as is safely possible, and the maintenance of

such therapy for as long as possible, with the expectation that a prolonged period

30 Medical Management of Type 1 Diabetes

of near-normal blood glucose levels will result in an even greater reduction in

the risk of both microvascular and macrovascular complications in patients with

type 1 diabetes.

GOALS OF TREATMENT

The physician and patient, with the diabetes management team and fam-

ily, must set treatment goals together. Although this concept seems obvious,

overlooking this often leads to failure of the treatment plan. The physician con-

vinced of the importance of stringent glycemic control in every case will be

frustrated by a patient who does not understand the need for, or is unable to

accept the goal or methods used to achieve, glycemic control. Conversely, the

patient who wants blood glucose levels to be normal all the time and is truly

willing to work for it will be frustrated by a physician who lacks the time, facili-

ties, or training to help achieve this goal or who is unable to guide the patient

to achieve this safely.

A good diabetes management team-patient treatment match requires open

communication and appropriate patient education. At the tightest end of the treat-

ment spectrum, the patient must have a sophisticated and practical understanding

of physiology and pharmacology when striving to maintain normal glucose levels

when, for example, exercising strenuously. At the looser end, knowledge may be

more rudimentary, but patients must at least know that to avoid diabetic keto-

acidosis (DKA), they may have to take extra insulin on sick days when appetite is

poor and common sense seems to dictate the reverse. Treatment must always be

individualized. Success in achieving small incremental steps is more likely to lead

to a greater improvement over the long run.

The physician and other team members should avoid seeming autocratic,

moralistic, or judgmental. They should work with the patient to try to under-

stand why goals are not met and empathize with the challenges faced by the

patient in paying daily attention to the never-ending demands of diabetes self-

care combined with other aspects of the patient’s life. It is paramount to work

with the patient to identify obstacles to the treatment plan so the patient can

actively participate in addressing them. It is important to encourage the best

incremental steps that are achievable without demanding the impossible, unsafe,

or impractical.

Setting individual patient glycemic targets should take into account the

results of prospective randomized clinical trials, most notably the DCCT. This

trial conclusively demonstrated that, in patients with type 1 diabetes, the risk

of development or progression of retinopathy, nephropathy, and neuropathy is

reduced 50-75% by intensive treatment regimens when compared with conven-

tional treatment regimens. These benefits were observed with an average glycated

hemoglobin (A1C) of 7.2% in intensively treated groups of patients compared

with an A1C of 9.0% in conventionally treated groups of patients. The reduc-

tion in risk of these complications correlated continuously with the reduction in

A1C produced by intensive treatment. This relationship implies that complete

normalization of glycemic levels may prevent complications. The nondiabetic

reference range for A1C in the DCCT was 4.0-6.0%.

Diabetes Standards and Education

Table 2.1 Summary of Glycemic Recommendations for Many

Nonpregnant Adults with Diabetes

A1C

<7.0%*

Preprandial capillary plasma glucose

70-130 mg/dL* (3.9-7.2

Peak postprandial capillary plasma glucose†

mmol/L)

• Goals should be individualized based on*

<180 mg/dL* (<10.0

• duration of diabetes

mmol/L)

• age/life expectancy

• comorbid conditions

• known CVD or advanced microvascular

complications

• hypoglycemia unawareness

• individual patient considerations

• More- or less-stringent glycemic goals may be

appropriate for individual patients

• Postprandial glucose may be targeted if A1C goals

are not met despite reaching preprandial glucose goals

†Postprandial glucose measurements should be made 1-2 h after the beginning of the meal, generally

peak levels in patients with diabetes.

Self-monitoring of blood glucose (SMBG) targets in the DCCT were

70-120 mg/dL (3.9-6.7 mmol/L) before meals and at bedtime and <180 mg/dL

(<10.0 mmol/L) when measured 1.5-2.0 h postprandially. Intensive insulin

therapy (at that time, a combination of human regular and human intermediate-

acting insulins, or pump therapy with human regular) was associated with a three-

fold increased risk of severe hypoglycemia.

Targets for children (e.g., 100-180 mg/dL before meals for infants to pre-

schoolers, 90-180 mg/dL for school-age children, and 90-130 mg/dL for

adolescents) are higher because of innate hypoglycemia unawareness and the

detrimental effect of hypoglycemia on the developing brain. Targets should be

further adjusted in any patient with a history of recurrent severe hypoglycemia

or hypoglycemia unawareness (e.g., 90-130 mg/dL [5.0-7.2 mmol/L] before

meals and 100-140 mg/dL [5.6-7.8 mmol/L] at bedtime). Since the DCCT, the

introduction of insulin analogs, enhanced provider experience, the widespread

use of multiple daily injections and insulin pumps giving smaller more frequent

doses of insulin and use of continuous glucose monitoring (CGM) appear to have

decreased severe hypoglycemia rates found in the DCCT while also decreasing

A1C values.

Individual treatment goals should take into account the patient’s capacity to

understand and carry out the treatment regimen, the patient’s risk for severe

hypoglycemia, and other patient factors that may increase risk or decrease ben-

efit, e.g., very young or old age, end-stage renal disease, advanced cardiovascular

or cerebrovascular disease, or other coexisting diseases that will materially affect

quality of life or shorten life expectancy.

The desired outcome of glycemic control in type 1 diabetes is to lower gly-

cated hemoglobin (A1C or an equivalent measure of chronic glycemia) so as to

achieve maximum prevention of complications with regard for patient safety.

32 Medical Management of Type 1 Diabetes

CLINICAL GOALS

Initial Goals

For the new-onset acutely decompensated patient or the previously diag-

nosed patient in poor control, goals should include

n eliminating ketosis

n returning to desirable body weight range by reversing water and extra

cellular electrolyte losses and replenishing lean body mass (protein and

intracellular electrolytes)

n eliminating obvious consequences of hyperglycemia, e.g., gross polyuria

and polydipsia, vaginitis or balanitis, recurrent infections, and visual blur-

ring due to reversible refractive changes

n avoiding cerebral edema in cases of DKA

Additional Goals

Once the initial goals have been achieved, additional goals should include

n near-normalization of blood glucose values and A1C with avoidance of

severe hypoglycemia

n preventing symptoms of hyperglycemia, such as excessive thirst and urinary

frequency, and disturbed sleep, school, work, social, or recreational activities

n preventing spontaneous and illness-induced ketosis

n maintaining weight within a desirable range

n stimulating catch-up growth and sexual maturation in children with poor

glycemic control

n maintaining normal growth rate in children and adolescents

n maintaining maximum exercise tolerance and stamina

n maintaining a sense of psychosocial well-being and normal initiative in

self-care

n minimizing self-treatable hypoglycemia and avoiding severe hypoglyce-

mic events resulting in seizures, accidents (e.g., while driving), and coma

n avoiding hospitalization

n for women, achieving normal fertility and pregnancy outcome

n sustaining normal family and marital relationships and sex life

n preventing diabetes-dictated or diabetes-oriented lifestyle (i.e., diabetes

controlling the patient rather than vice versa)

n for youth, planning for and achieving transition to adult diabetes care

In addition to the educational and clinical goals discussed above, patients

and the diabetes management team should individualize glycemic control goals.

It is desirable to aim for near-normalization of blood glucose, if this can be

achieved without significant serious side effects (Table 2.2). All patients should

be given the opportunity to pursue these goals using a flexible, individualized

diabetes management program, based on an assessment of potential risks and

benefits.

Diabetes Standards and Education

Table 2.2 Plasma Blood Glucose and A1C Goals for Type 1

Diabetes by Age Group

Plasma blood glucose

goal range (mg/dL)

Values by

Before After

age (years)

meals meals

A1C

Rationale

Infants

through pre-

100-180

110-200

<8.5% (but >7.5%) High risk of

school age

hypoglycemia

(0-6)

School age

Risk of hypoglycemia and

90-180

100-180

<8%

(6-12)

relatively low risk of

complications prior to

puberty

Adolescents and

90-130

90-150

<7.5%

young adults

• Risk of severe

(13-19)

hypoglycemia

•

Developmental and

psychological issues

•

A lower goal (<7.0%) is

reasonable if it can be

achieved without

excessive hypoglycemia

Key concepts in setting glycemia goals:

• Goals should be individualized and lower goals may be reasonable based on benefit-risk

assessment.

•

Blood glucose goals should be higher than those listed above in children with frequent

hypoglycemia or hypoglycemia unawareness.

•

Postprandial blood glucose values should be measured when there is a discrepancy

between preprandial blood glucose values and A1C levels.

Assessment of A1C

During diabetes visits, glycemic control is assessed by results of glycohemo-

globin tests. Many different types of glycohemoglobin assay methods were avail-

able in the past, differing considerably with respect to the glycated components

measured, interferences, and nondiabetic range. Glycated hemoglobin A_1c (A1C)

has become the preferred standard for assessing glycemic control, and in 1996,

the National Glycohemoglobin Standardization Program (NGSP) was formed

to standardize the A1C test to DCCT values. Since then, A1C measurements in

North America have been almost universally standardized to the DCCT assay

range.

The International Federation of Clinical Chemistry (IFCC) developed

a standard for A1C that results in a measurement of concentration (mmol

A1C/mol HbA) rather than percent and a reference range that is different

34 Medical Management of Type 1 Diabetes

than the DCCT standard. A consensus between the IFCC and world diabetes

organizations, including the American Diabetes Association, suggests that in

medical journals and in the clinical arena, A1C results will be reported in both

ways: the IFCC concentration and the DCCT-standardized A1C (as percent).

Mmol/mol is the Systeme International (SI) unit. In the US, most lab reports

do not use SI units, so it is unclear whether clinically these units will become

more common. Although small studies had suggested this to be the case for

type 1 populations, a multicenter study in subjects with type 1, type 2, and no

diabetes; of multiple ethnic groups; and on multiple types of diabetes therapies

confirmed that there is a close association of A1C with the mean blood glucose

over the prior 2-3 months across the entire study population. This has led

some laboratories in the US to report, on request, both A1C as a percentage

and estimated average glucose (eAG).

In the past, when data compiled from diabetes specialty clinics in North

America and Europe were analyzed, patients with type 1 diabetes have shown

median A1C values (DCCT standard) of 8.0-9.0%. These correspond to mean

blood glucose levels of ~200 mg/dL (~11.1 mmol/L). Adolescents with type 1

diabetes generally average 0.5-1.0% higher values and a blood glucose that is

20-40 mg/dL (1.1-2.2 mmol/L) higher than adults. Hemoglobin variants have

the potential to cause falsely low or high A1C readings, especially with older

assays. In 2008, only ~5% of assays done in labs in the US give spurious results

with Hb, AS, or AC. A list of assays and whether or not they are accurate in

patients with hemoglobin variants can be found on the NGSP website (http://

www.ngsp.org/prog/index.html ).

Assessment and Goals of Glycemic Control

In addition to A1C, during diabetes visits, individual glucose values from

SMBG and CGM can be obtained from log books, uploading glucose meters

and CGM devices, or glancing through the stored data on the meter and CGM

screens. Diabetes control is assessed by the patient at home via SMBG, CGM,

home A1C testing, and urine or blood ketones.

The premeal SMBG and CGM goal for optimal treatment is similar to the

70-120 mg/dL (3.9-6.7 mmol/L) goal used in the DCCT. Over the course of that

study, >75% of morning (fasting) glucose levels were >120 mg/dL (>6.7 mmol/L).

In practice, most pre-breakfast glucose levels will be between 80 and 160 mg/dL

(4.4 and 8.9 mmol/L) in patients with A1C values <7.0%.

The following levels of glycemic control are appropriate for patients with

type 1 diabetes.

n In all pregnant women and women attempting to conceive, seek “strin-

gent” biochemical goals of intensive treatment (A1C <6.0%; preprandial,

HS, and overnight blood glucose 60-99 mg/dL [3.3-5.4 mmol/L]; and

peak postprandial blood glucose 100-129 mg/dL [5.4-7.1 mmol/L]) by

methods detailed below (see Pregnancy, page 161).

n In nonpregnant patients who are well informed about the risks and poten-

tial benefits of intensive insulin therapy and are motivated and suitably

educable, seek an optimal level of control (<7.0% A1C, or in selected

patients as close to normal as possible), if achievable without significant

Diabetes Standards and Education

serious side effects. This is accomplished with average blood glucose levels

of 110-150 mg/dL (6.1-8.3 mmol/L). Day-to-day fluctuations in blood

glucose level are unavoidable, and both patients and providers should

focus on patterns. If the patient does not sense or respond to hypoglyce-

mia or has frequent hypoglycemia, goals should be set higher to reduce

the risk of severe hypoglycemia.

Results of Optimal Control

At an optimal level of control, patients are entirely asymptomatic and may

perceive a very good or excellent sense of well-being, energy, and exercise capac-

ity and less disease-related anxiety compared with maintenance at poor control.

They may also express a greater sense of control over the management of the

disease if they use a flexible, individualized management program. However, they

may experience increased mild self-treated and also severe hypoglycemic episodes.

Some patients may feel excessively burdened by the required frequent monitoring,

insulin administration methods, and constant dietary adherence. Negotiation (and

renegotiation) of mutually acceptable goals will reduce the chances that patients

will abandon reasonable self-care. In fact, treatment of type 1 diabetes always

involves a negotiated therapeutic alliance between patient (and family) and the

diabetes management team.

CONCLUSION

For patients with type 1 diabetes, the long-term benefits of optimal diabe-

tes management appear extremely promising. A flexible, individualized diabetes

management program utilizing the principles of intensive insulin therapy should

be encouraged in almost all type 1 diabetes patients from onset. These benefits

must be balanced in each patient against actual risks and costs. The diabetes

management team together with the patient should set treatment goals on the

basis of their own best judgment regarding individual patient capabilities and

understanding.

BIBLIOGRAPHY

American Diabetes Association: Standards of medical care for patients with

diabetes mellitus (Position Statement). Diabetes Care 26 (Suppl. 1):S33-S50,

2003

American Diabetes Association: Tests of glycemia with diabetes (Position State-

ment). Diabetes Care 26 (Suppl. 1):S106-S108, 2003

DCCT/EDIC Research Group: Intensive diabetes therapy and carotid intima-

media thickness in type 1 diabetes. N Engl J Med 348:2294-2303, 2003

DCCT/EDIC Research Group: Retinopathy and nephropathy in patients with

type 1 diabetes four years after a trial of intensive therapy. N Engl J Med

342:381-389, 2000

36 Medical Management of Type 1 Diabetes

DCCT Research Group: The effect of intensive treatment of diabetes

on the development and progression of long-term complications in

insulin-dependent diabetes mellitus. N Engl J Med 329:977-986, 1993

DCCT Research Group: The relationship of glycemic exposure (HbA_1c) to the

risk of development and progression of retinopathy in the Diabetes Control

and Complications Trial. Diabetes 44:968-993, 1995

Klein R: Hyperglycemia and microvascular and macrovascular disease in diabe-

tes. Diabetes Care 18:258-268, 2005

Nathan D, Cleary P, Backlund JY, Genuth SM, Lachin SM, Orchard TJ,

Raskin P, Zinman B: Intensive diabetes treatment and cardiovascular disease

in patients with type 1 diabetes. N Engl J Med 353:2643-2653, 2005

National Cholesterol Education Program (NCEP) Expert Panel on Detec-

tion, Evaluation, and Treatment of High Blood Cholesterol in Adults

(Adult Treatment Panel III): Executive summary of the Third Report of the

National Cholesterol Education Program (NCEP) Expert Panel on Detec-

tion, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult

Treatment Panel III). JAMA 285:2486-2497, 2001

Pirart J: Diabetes mellitus and its degenerative complications: a prospective

study of 4,400 patients observed between 1947 and 1973. Diabetes Care

1:168-188, 252-263, 1978

Reichard P, Nilsson BY, Rosenqvist U: The effect of long-term intensified

insulin treatment on the development of microvascular complications of

diabetes mellitus. N Engl J Med 329:304-309, 1993

Rohlfing CL, Wiedmeyer HM, Little RR, England JD, Tennill A, Goldstein

DE: Defining the relationship between plasma glucose and HbA_1c: analysis

of glucose profiles and HbA_1c in the Diabetes Control and Complications

Trial. Diabetes Care 25:275-278, 2002

Santiago JV: Lessons from the Diabetes Control and Complications Trial.

Ðiabetes 42:1549-1554, 1993

Silverstein J, Klingensmith G, Copeland K, Plotnick L, Kaufman FR, Laffel L,

Deeb L, Grey M, Anderson B, Clark N: Care of children and adolescents

with type 1 diabetes mellitus: a statement of the American Diabetes Associa-

tion. Diabetes Care 28:186-212, 2005

Skyler JS: Tactics in type 1 diabetes. Endocrinol Metab Clin North Am 26:647-

657, 1997

Diabetes Standards and Education

PATIENT SELF-MANAGEMENT EDUCATION

iabetes management is a team effort. Physicians, nurses, dietitians, phar-

macists, and other health care professionals contribute their expertise to

the design of therapeutic regimens that will enable patients to achieve

the best possible metabolic control. The patient is at the center of the team and,

supported by his or her family, has responsibility for day-to-day implementation

of the treatment plan. In the case of children, the caregivers take on this respon-

sibility. Therapy will be most effective if the patient understands the regimen,

is not ambivalent about the value, and has mastered the skills to do required

tasks correctly. Therefore, the clinical management of diabetes relies heavily on

patient self-management.

The importance of patient education is underscored by the DCCT, which

demonstrated that intensive treatment of diabetes, with great demands in patient

self-management, can prevent or delay the long-term complications of diabe-

tes. Because intensive therapy brings an increased risk of hypoglycemia, patient

education is critical in providing safety. In addition, diabetes self-management

training has been shown to improve A1C with as much as a 0.76% reduction

immediately after education is delivered. The effect of diabetes education on A1C

is directly correlated to the amount of contact time spent between the educator

and the patient; 23.6 hours of educator contact has been shown to decrease A1C

by 1%, an amount known to be associated with a dramatic reduction in micro-

vascular disease.

This section provides an overview of diabetes patient education, including

information on the principles, process, content, and guidelines for incorpo-

rating education into clinical practice. Several terms, “including diabetes self-

management education” and “diabetes self-management training,” are used to

describe patient education in diabetes. They will be used interchangeably in

this manual. However, for reimbursement purposes, “diabetes self-management

training” is the preferred terminology.

GENERAL PRINCIPLES

The goal of diabetes self-management education is to provide patients with

the knowledge, skills, and motivation to incorporate ongoing diabetes self-care

into their daily lives and to actively collaborate with the diabetes health care team

in managing the disease. To meet this goal, diabetes education must include

teaching patients the new information they need to know about the diabetes dis-

ease process, training them in the various skills they need for their prescribed

treatment plan and procedures, assisting them in developing strategies to fit the

regimen into their lifestyle, and helping them reconcile diabetes care with their

quality of life so they are motivated to manage their disease. To accomplish this,

diabetes self-management education should be responsive to the unique and indi-

vidual needs of the patient and equally accessible to all patients regardless of

economic, social, and environmental circumstances.

38 Medical Management of Type 1 Diabetes

Table 2.3 Process of Diabetes Self-Management Education

Assessment

Gathering information, both subjective and objective, to Identify a

patient’s individual education needs

Planning

Designing education for the patient based on the assessment, includ-

ing topics, goals for education, and selection of teaching/learning

strategies

Implementation Providing the planned education in an environment that supports

learning

Documentation Documenting the educational activities to inform other members of

the diabetes management team and to record the care provided

Evaluation

Measuring the impact of education by testing knowledge and skills

and by evaluating behavioral and metabolic outcomes

Reassessment

Periodically reviewing clinical and nonclinical information about the

patient to identify new needs and re-educate as needed

Ideally, a diabetes management team should be involved in patient educa-

tion. In the Diabetes Attitudes, Wishes and Needs (DAWN) study, a survey

conducted among patients, nurses, and physicians, it was found that nurses

provide better education, spend more time with patients, are better listeners,

and get to know patients better than physicians. In addition, patients had bet-

ter outcomes when they had access to a nurse, but less than 50% of patients

surveyed said they had such access. Many physicians do not have a diabetes

education team available in their practice setting. They need to refer patients,

if possible, to a diabetes education program or to diabetes educators. Physicians

can develop a team approach by collaborating with diabetes educators working

in diabetes education programs. The American Diabetes Association’s Educa-

tion Recognition Program identifies diabetes education programs that meet

the National Standards for Diabetes Self-Management Education through a

Medicare-approved accreditation process. A list of active ADA Recognized

programs is available on the Association’s website and can be accessed at www

.diabetes.org/findaprogram.

Diabetes self-management education is a planned process that requires

resources, including time, materials, space, and professional expertise (Table

2.3). The knowledge and skills patients need to implement their treatment regi-

men and sustain a lifetime of living with diabetes cannot be acquired during a

quick interaction on the day of diagnosis or in a single instructional session

in a physician’s office or any other setting. Moreover, patient education is an

ongoing component of diabetes care, not a one-time encounter. Despite this

emphasis on diabetes education, self-management programs have been found

to be underutilized in a number of studies, with relatively fewer patients having

ongoing contact with educators.

For the newly diagnosed patient, a staged approach to education should be

used, with the initial teaching focused on the critical information or “survival

skills” that will enable the individual, or caregiver, to implement the regimen at

Diabetes Standards and Education

Table 2.4 Basic Education at Diagnosis: Survival Skills

Topics and the critical knowledge and skills patients need to manage their diabetes at

home include:

General facts

Explain the need for daily insulin injections and that treatment of

diabetes involves insulin, diet, exercise, and SMBG

Medications

Measure insulin dosage accurately, inject correctly, and under-

stand timing of injections and how to handle insulin and supplies

Nutrition

Explain the relationship of food, insulin, and blood glucose and

the amount of food, type of food, and times to eat to maximize

blood glucose control

Exercise

Explain the relationships of exercise, food, and insulin and how

to prevent hypoglycemia from exercise

Monitoring

Perform accurate SMBG and urine or blood ketone tests

Hyperglycemia and

Differentiate the signs and symptoms of high and low blood

hypoglycemia

glucose levels and know what actions to take for each situation;

know when to seek immediate medical assistance for intercur-

rent illness, hyperglycemia, or ketonuria

Use of the health

Identify how to obtain insulin supplies, whom to call for

care system

professional advice, and how to get help in an emergency

home (Table 2.4). Once the patient is comfortable with the fundamental com-

ponents of the regimen, teaching can be expanded to provide more in-depth

information and to introduce additional topics. Continuing education across

the life span provides opportunities for learning new management techniques;

for making adjustments in the regimen to accommodate lifestyle changes,

growth, and aging; to consider adding new therapies or technologies; and to

sustain positive clinical and quality-of-life outcomes achieved.

To be effective, diabetes self-management education must be individual-

ized. Teaching methods, however, need not be limited to individual instruction.

Group classes and self-study methods can supplement individual instruction and

offer advantages in meeting different learning styles and in efficient use of teach-

ing time. Information from all sources must be consistent, whether provided by

different health professionals or from diverse instructional materials. Therefore,

all members of the diabetes management team need to be aware of the content of

the education program.

SELF-MANAGEMENT EDUCATION PROCESS

Diabetes self-management education is a systematic process that starts with

an assessment of individual educational needs to guide the planning of teaching/

learning strategies, followed by implementation of the plan and documentation

of the process, and concluding with evaluation of learning as evidenced by

behavior change and health outcomes. Although terms may be different, the

40 Medical Management of Type 1 Diabetes

process mimics the traditional steps clinicians use to diagnose and treat patients.

Understanding the commonalities of patient education and medical care facili-

tates integration of education into the clinical management of diabetes.

There are guiding principles for diabetes education. These principles are

supported by numerous studies and include:

1. Diabetes education is effective in improving clinical outcomes and qual-

ity of life,

2. Diabetes self-management education has evolved from didactic presenta-

tions to theoretically based empowerment models,

3. There is no one best methodology, and effective programs have incorporated

behavioral and psychosocial strategies, culture and age-specific program-

ming, and individual and group sessions,

4. Ongoing support is important for sustained benefit, and

5. Behavioral goal-setting is an effective strategy to support self-management

behaviors

Assessment

The first step in the educational process is an assessment to obtain clinical,

psychosocial, and educability data to determine an individual education plan.

Information obtained in this assessment can guide both treatment and education

decisions. For example, if assessment shows that the individual has limited learn-

ing skills, treatment with a simple insulin regimen versus a complex algorithm

of dose adjustments would be appropriate, with educational strategies including

selection of pictorial instructional materials, return demonstration, and a plan for

evaluating accurate performance at home.

The education assessment also focuses on the three key areas of the learn-

ing process: cognitive/knowledge, psychomotor/skills, and affective/attitude.

To develop teaching strategies, the educator needs to evaluate each patient to

determine specific knowledge that needs to be acquired; skills that need to be

mastered; and personal attitudes toward diabetes, health care, and life skills and

experiences that will predict the behavior change potential since most aspects of

diabetes self-care and management require behavior changes.

As a general framework, the educational assessment should include

n demographic information: age, gender, level of education, occupation,

and family status; and for children, this information must be obtained

about parents or caregivers

n medical history: height; weight; BMI; blood pressure; blood glucose values

(A1C, fasting, plasma glucose, and self-monitoring results); blood lipid val-

ues; medications (prescribed and over-the-counter); allergies; other medical

problems; general health status, including smoking, alcohol consumption,

sexual activity, and use of social drugs; health service or resource utiliza-

tion; and for children, developmental capabilities, prior growth records and

pubertal stage

n diabetes history: type of diabetes; duration of diabetes; current treatment

plan, including medication, diet, exercise, monitoring, and problems with

Diabetes Standards and Education

adherence; acute and chronic complications; family history; previous dia-

betes education; and for children, diabetes management plan at school or

childcare

n dietary habits: meal times and locations, snacking patterns, food prefer-

ences, resources for food preparation, patterns suggestive of disordered

eating, and previous diet instructions (note that medical nutrition therapy

includes a more detailed history; see Nutrition, page 98)

n physical activity: work/school activity, recreational activity

n social history: information on household, extended family, social network,

cultural factors, religious practices, health beliefs, and current health

practices

n economic profile: income, health insurance, transportation resources, and

neighborhood environment

n lifestyle: activities of daily living, including work, school, and leisure time;

for children, information on after-school, weekend, and summer activities

n psychosocial status: feelings about diabetes, personal relationships (with

spouse, partner, parents, family, peers), developmental stages in life-cycle,

history of sleep or eating disorders, stress, anxiety, or depression; health

goals

n education factors: functional health literacy, computational skills, readi-

ness to learn, preferred learning methods, visual acuity, hearing loss, dex-

terity; life experiences; and for children, developmental stage

n knowledge and skill level in each of the nine content areas of the National

Standards for Diabetes Self-Management Education

Additional information will be required to develop educational plans to meet

the idiosyncratic needs of individual patients. However, the extent and complete-

ness of the assessment will be determined by the patient as he or she presents for

education. For example, a newly diagnosed patient overwhelmed by the diagnosis

may not be ready to digest the need for acquiring all these data before a ses-

sion. The ultimate goal is to completely assess the patient over time. Parts of the

complete assessment can be deferred until the patient is fully able to participate

and provide helpful and the most beneficial information for education planning.

Assessment should therefore be dynamic, ongoing, and dictated by patient readi-

ness, in order to obtain the most beneficial information to guide education. Also,

as with nutrition, each member of the diabetes management team will use a more

extensive assessment specific to their area of expertise.

Patient autonomy should be supported by understanding the patients’

diabetes-related priorities and needs, acknowledging patients’ feelings and

experiences, facilitating meaningful self-management choices, offering relevant

information, and avoiding controlling patients’ behavior.

Planning Educational Strategies

The assessment identifies the topics that need to be included in the educa-

tion plan and teaching methods that would be most effective. From this analysis,

42 Medical Management of Type 1 Diabetes

educational goals are developed for each patient. The educational goals must cor-

respond with therapeutic goals established by the diabetes management team and

diabetes management goals set by the patient. If the diabetes management team

is focused on normalization of blood glucose and the patient is focused on mak-

ing a minimum number of lifestyle changes, teaching will not be effective until

there is agreement. Once goals are established, measurable behavioral objectives

are developed with the patient to clearly identify steps that will be used to achieve

these goals.

The education plan delineates what is to be taught when, how, where, and by

whom. There are numerous teaching strategies that can be used with a patient

(Table 2.5). For a newly diagnosed patient, the plan would specify topics that need

to be covered immediately to provide the patient with the “survival skills” neces-

sary to manage his or her diabetes at home (Table 2.4). Teaching methods could

include

n one-on-one sessions with the dietitian to develop a meal plan

n one-on-one sessions with the diabetes educator to learn insulin injection

and monitoring techniques

n observation of patient injection and monitoring skills by staff nurses

n a videotape describing pathophysiology

n Internet education modules

The plan would include methods for evaluating learning accomplished in the

initial phase, steps to reinforce what has been taught, and resources for obtaining

in-depth education within a reasonable time frame.

Implementation

Teaching can take place in a classroom, at bedside, in an office, in the

home, in the cafeteria, in a community facility, or in a number of other settings.

Whatever space is used, it is critical that the environment support learning and

reinforce the importance of the educational process as part of diabetes care.

There should be adequate lighting and furnishings and minimal distractions.

Education sessions should be scheduled at specific times. Scheduling will help

ensure that teaching and learning take place and help establish the concept that

education is a specific part of diabetes care. The same measures used to rein-

force routine clinical appointments should be used, including written informa-

tion giving the appointment time, location (with directions if needed), and the

name(s), telephone number(s), or Internet addresses of the educator(s).

Documentation

Documentation of education is as important as documentation of treatment

procedures. It provides a means of communication among the diabetes manage-

ment team as well as substantiating the provision of educational care. Documen-

tation can also provide a reference for reinforcing educational and behavioral

objectives necessary to accomplish treatment goals by other members of the dia-

betes team.

Diabetes Standards and Education

Table 2.5 Teaching Strategies

Methods

n Individual instruction: education can be tailored to individual learning needs and focused

on specific details of patient’s self-management plan; can also accommodate patient-

specific learning barriers like vision problems or cognitive challenges

n Group classes: efficient use of educator time, patients benefit from social support and

peer learning

n Self-study: flexible, allows patient to pace learning, educator should monitor and evalu-

ate progress

n Can be mastery-based

Techniques

n Short lecture: effective for presenting new information

n Discussion: allows patient to personalize information, ask questions, disclose feelings,

and share experiences

n Skills training: provides “hands on” learning; educator demonstrates, patient practices

then performs a return demonstration and receives feedback from educator

n Problem-solving: allows patients to integrate information on several topics, such as diet,

insulin, and exercise, and to test their knowledge in hypothetical situations

n Role-playing: can be used to reinforce learning (patient plays educator role), to practice

social skills (explaining diabetes to friends), and to explore personal problems (family

stress)

n Case studies: provide an objective approach to learning that can be used for planning,

for problem-solving, and to help patients identify errors they are making in their diabetes

self-management

n Self-assessment: blood glucose records, food diaries, and exercise logs can be used to

help patients recognize problems in their diabetes self-management and often to identify

solutions

n Contracting/goal-setting: used to get patient buy-in on the specifics of changing

behavior. Patient-driven, plan for reevaluating contracts or goals to assess degree of

achievement, acknowledge successes, and reinforce needed information. AADE-7 is a

framework for contracting/goal-setting

n Demonstrate projects: dining out, cooking classes, supermarket trips offer practical

ways to apply complex information

Materials

n Printed materials: can be used to reinforce teaching, for self-study, and as an information

resource for future needs (e.g., sick-day guidelines)

n Audio and visual aides: slides, films, overheads, audiotapes and videotapes, food mod-

els and labels, sample diabetes products, and dolls and puppets are effective in enhanc-

ing learning

n Interactive learning programs: available in printed, audio, visual, and computer formats;

allow individuals to learn at their own pace, with frequent evaluation to provide feedback

on learning

n Games: crossword puzzles, board games, and group games introduce fun into the edu-

cational process while enhancing participant learning

n A case study with questions to evaluate learning and problem-solving skills

n Conversation maps: very effective in stimulating “conversation” and directing teaching to

patient-expressed needs

44 Medical Management of Type 1 Diabetes

Documentation can be included in progress notes in the patient’s medical

chart or electronic medical record, maintained in education charts or an elec-

tronic database, or written in correspondence and reports. Whatever method of

documentation is used, a permanent record of a patient’s educational experience

must be maintained.

Evaluation

The effectiveness of the educational plan is evaluated in several ways. First,

assessment of learning will provide measures of knowledge gained, skills acquired,

and changes in attitudes. This type of evaluation often is included in the imple-

mentation process to allow for reinforcement in areas where the patient exhibits

weaknesses. It is typically done in the short run, in the immediate post-education

phase. Periodic reassessments will provide measures of lapses in knowledge, skills,

or attitudes that can be remedied with a refresher course. Another evaluation pro-

cedure measures changes in behavior. This evaluation takes place some time after

education (1-3 months) to measure whether the short-term attitude changes and

behavior modifications are maintained and have resulted in sustained behavior

change. The behavioral objectives developed during the planning phase may be

used, or a different set of objectives can be set at the completion of education as

an outgrowth of the learning process. A third approach evaluates the effectiveness

of education by examining treatment goals, such as lower A1C, improvement in

quality of life evidenced by minimal hypoglycemia, or absence of ketoacidosis.

All forms of evaluation yield an assessment of additional educational needs of the

patient.

CONTENT OF DIABETES SELF-MANAGEMENT EDUCATION

Topics to be included in diabetes patient education are numerous and vary

according to type of diabetes, patient age, and other individual characteristics. The

National Standards for Diabetes Self-Management Education specify that pro-

grams should be equipped to provide information in nine core content areas. The

suggested topics are listed below with basic teaching points for type 1 diabetes:

n Describing the diabetes disease process and treatments: Type 1

diabetes is a chronic metabolic disorder in which the body no longer

produces insulin required to use food for energy. The loss of insu-

lin production is due to an autoimmune process that results from an

interaction of genes and environmental triggers. Lack of insulin can be

life-threatening. Daily insulin injections are essential and need to be bal-

anced with meals and physical activity to manage diabetes. Understand-

ing the interactions among the three (food, insulin, and activity) and their

impact on blood glucose levels is important in making self-management

decisions. Self-monitoring values provide information that can be used to

make adjustments in one or more of the three therapeutic agents.

n Incorporating nutritional management into lifestyle: Food is an

important part of diabetes treatment and health. The amount, type,

Diabetes Standards and Education

and timing of meals and snacks must be balanced with insulin and

exercise to maintain good blood glucose control. Meal planning should

be individualized to reflect food preferences and daily schedules, pro-

vide optimum nutrition, maintain a healthy weight, and make diabetes

self-care as effective as possible.

n Incorporating physical activity into lifestyle: Physical activity is rec-

ommended for health and diabetes management. Physical activity can

affect blood glucose levels and other health parameters like blood pres-

sure, weight, and stress, usually by lowering them. Exercise for purposes

of diabetes education can be characterized as any tolerable increase in

baseline activity. Planning for exercise can prevent hypoglycemia that

may occur during or after exercise.

n Using medication(s) safely and for maximum therapeutic effective-

ness: Insulin must be taken daily as prescribed. It is important to know

the type and amount of insulin to be taken and times to administer insu-

lin and to understand the action and duration of the prescribed insulin.

Correct techniques for drawing up and injecting insulin with a syringe or

pen device are critical to ensure that the dose is accurate. There are dif-

ferent types of insulin regimens, from fixed 2-3 injections, to basal bolus

therapy with multiple daily injections or insulin pump therapy. Family

members, close friends, coaches, teachers, co-workers, and others who

closely interact with the diabetes patient on insulin need to know how to

administer glucagon in the event of severe hypoglycemia.

n Monitoring blood glucose and other parameters and interpreting and

using the results for self-management decision-making: Proper tech-

nique is crucial to achieve reliable results. Blood glucose monitoring results

can be used to assess the effectiveness of the treatment regimen, identify

low blood glucose levels requiring treatment to prevent hypoglycemia,

indicate high blood glucose levels possibly associated with illness, show the

effect of different meals and activities on blood glucose, and guide deci-

sions on when to contact health care providers. Proper technique is crucial

to achieve reliable results. The downloading of meter data can help with

data management. CGM has an additional role in showing trends and pat-

terns and alerting at set or predictive thresholds. Urine or blood testing for

ketones is required during times of physical or emotional stress and may be

necessary during pregnancy.

n Preventing, detecting, and treating acute complications (hypogly-

cemia, hyperglycemia, and illness): Hypoglycemia comes on quickly.

Therefore, it is important to recognize the signs and symptoms of hypogly-

cemia and to know how to prevent and treat it (Table 2.6). Hyperglycemia

that cannot be explained by diet or another aspect of the regimen (e.g.,

decrease in exercise or inadequate insulin delivery or amount) may indicate

illness. Patients with type 1 diabetes can develop DKA when ill. Therefore,

guidelines for sick days need to be followed carefully (Table 2.7). Family

members, friends, coworkers, and teachers need to know how to respond in

case of emergencies.

46 Medical Management of Type 1 Diabetes

Table 2.6 Sample Patient Guidelines for Treating Mild

Hypoglycemia: 15/15 Rule

If blood glucose falls below 70 mg/dL:

n Eat 15 g carbohydrate, preferably in the form of glucose products

n Wait 15 min—retest, and if blood glucose remains <70 mg/dL, treat with another

15 g carbohydrate

n Repeat testing and treating until blood glucose returns to normal range

n If >1 h to next meal, add additional 15 g carbohydrate to maintain blood glucose in nor-

mal range

Sources of carbohydrate

Glucose products (preferred):

Glucose tablets

4-5 g/tablet

Glucose gel

15 g/dose

Insta-glucose gel

24 g tube/one-dose tube

Food/beverages (use if above not available),

15-g portions:

Graham crackers

Saltine crackers

Raisins

2 Tbsp

Syrup or honey

1 Tbsp

Juice (apple/orange)

1/2 cup

Soft drink (regular)

1/2 cup

Skim milk

1 cup

Ginger ale

3/4 cup

Note: Severe hypoglycemia needs to be treated by someone knowledgeable about diabetes. Guide-

lines should be available in schools and work sites. If the patient cannot swallow well, glucagon must

be used instead of oral treatment.

n Preventing, detecting, treating, and rehabilitation of chronic com-

plications: Chronic complications are a serious concern in diabetes. Steps

that can reduce the risk of complications include maintaining blood glu-

cose levels as near to normal as feasible, not smoking, having annual eye

exams, controlling blood pressure and blood lipid levels, assessing urine

microalbumin excretion, and taking preventive care of feet.

n Developing personal strategies to address psychosocial issues: Fear,

anger, and denial are common responses to the diagnosis of diabetes and

other stages of the disease process. The day-by-day demands of diabetes

management can be frustrating. Stress may cause problems with blood

glucose control. Coping skills, stress reduction techniques, and profes-

sional counseling can help the patient handle the psychosocial impact

of diabetes. Type 1 diabetes affects the whole family. Family members,

friends, coworkers, and teachers need to know about diabetes and how

to support the regimen. Adolescents must not be left to manage diabe-

tes without some degree of parental supervision. Camps and support

Diabetes Standards and Education

Table 2.7 Sample Patient Guidelines for Sick-Day Management

Illness can make diabetes more difficult to manage. Even when you do not feel well, you

must take your insulin, test blood glucose and urine or blood ketones, drink fluids, and eat

if you can. Eating food is less important. You will need ketone strips and fluids that can be

a source of glucose and electrolytes. Therefore, planning ahead for sick days is important.

The following guidelines will help you during mild illnesses.

Monitoring

Blood glucose and urine (or blood) ketones need to be tested frequently during illness,

often every 2-4 h. Test for ketones if you have unexplainable high blood glucose values

>250 mg/dL or if you feel ill, even if blood glucose values are normal. Write down the values

and call a member of your diabetes management team when premeal blood glucose values

stay >250 mg/dL and/or when you measure moderate or large ketones.

Insulin

Never stop taking insulin even if vomiting and unable to eat. Your body often needs more

insulin during illness. Therefore, your health care professional may ask you to take addi-

tional insulin (a correction bolus) according to results of blood glucose monitoring.

Food and fluid intake

Use small meals and eat more frequently when you are ill. Soft foods or liquids are often

tolerated best. Eating about 10-15 g carbohydrate every 1-2 h is usually sufficient. Foods

and beverages containing about 15 g carbohydrate include

1/2 cup regular gelatin

3/4 cup regular ginger ale

1/2 cup vanilla ice cream

1/2 cup regular soft drink

1/2 cup custard

1/2 cup orange or apple juice

1 regular double Popsicle

1 cup Gatorade

1/2 cup applesauce

1 cup clear soup

Fluid intake is essential during illness. If vomiting, diarrhea, or fever is present, take small

quantities of liquids every 15-30 min. Clear broth, tea, and other fluids can supplement

liquids containing carbohydrate.

Seek medical attention when you have

n Fever >100ºF

n Severe abdominal pain

n Persistent diarrhea

n Other unexplained symptoms

n Vomiting and are unable to take fluids for >4 h

n Illness that persists over 24 h

n Blood glucose levels that are difficult to control

with or without ketones (see information above

on monitoring)

Physician’s #

Pharmacy #

48 Medical Management of Type 1 Diabetes

groups, including online diabetes networks, can help with denial and

isolation.

n Developing personal strategies to promote health and behavior

change: Most aspects of diabetes management require changes in behav-

ior. Behavior change is not simply willpower. Strategies such as goal set-

ting, contracting, and developing problem-solving techniques based on

patient experience are helpful in changing habits to reduce health risks

and improve diabetes control. Risk factors for diabetic complications,

including cardiovascular disease, should be addressed. Achieving opti-

mal glucose control may deter the complications of diabetes, including

those occurring during pregnancy. Women with type 1 diabetes need to

achieve excellent blood glucose control before becoming pregnant (opti-

mally for 3 months before conception) and maintain tight glucose control

throughout pregnancy; however, tight control brings an increased risk of

hypoglycemia. Individuals with diabetes need to be responsible for their

diabetes management, which includes working with their diabetes man-

agement team to select the treatment plan that meets their personal goals

for health. Because changing behavior underlies most aspects of diabetes

self-management, presenting the content areas in action oriented, behav-

ioral terms will help to underscore the importance of active patient par-

ticipation in diabetes care and management.

ADDITIONAL TOPICS OF IMPORTANCE FOR TYPE 1 DIABETES

n Using the health care system and community resources: People with

diabetes need to be good consumers of the health care system and of com-

munity resources. Ongoing versus episodic care is important. Contact

information, including phone numbers and Internet addresses of diabetes

management team members and emergency services, should be readily

available for use by family and friends as well as the individual with diabe-

tes. Identifying accessible resources in the community and on the Internet

for supplies, services, information, and support groups makes day-to-day

diabetes management easier and helps the patient to maintain positive

outcomes over time.

n Wearing an identification bracelet or necklace: This is strongly

encouraged and recommended at all times so that having diabetes can be

quickly ascertained in the event of acute crises such as unconsciousness or

motor vehicle accident.

n Driving a motor vehicle: Special care should be taken to prevent hypo-

glycemia while driving a car, truck, motorboat, or any other powered

vehicle. Blood glucose levels should be checked before driving, especially

if the last meal was more than 3 h earlier or if the trip will be long, and

low blood glucose values should be treated appropriately (Table 2.6).

Supplies for SMBG and treating hypoglycemia should be carried in the

vehicle at all times. If symptoms of hypoglycemia occur, driving should

stop immediately and not be resumed until blood glucose levels are in the

normal range for at least 10 min.

Diabetes Standards and Education

n Traveling: Insulin and diabetes supplies sufficient for the entire trip need

to be carried with the traveler and not put into checked baggage. Food

to treat hypoglycemia and for a meal that may be delayed by late arrival

should be left in place or carried for security reasons. Additional prescrip-

tions should be carried as well, in case the need to purchase supplies does

occur.

n Working: Jobs that have erratic schedules, have long periods between

meals, lack the flexibility to stop work and test blood glucose levels, or

have other conditions make diabetes management more challenging.

The Americans with Disabilities Act requires employers to make reason-

able accommodations for employees with disabilities, including diabetes.

The person with diabetes along with his or her supervisor and diabetes

management team can identify ways to modify a job to accommodate the

demands of work and diabetes management.

n Orientation and continuing education for school personnel:

Children with diabetes in school are protected by Section 504 of the

Rehabilitation Act of 1973, the Americans with Disabilities Act (ADA),

and Individuals with Disabilities Education Act (IDEA) so that there is a

medically safe environment and equal access to educational opportunities

and school-related activities. The Diabetes Medical Management Plan,

devised by the health care team and the student/parents, outlines what

must be done in school with regard to administration of medication, moni-

toring, nutrition, activity, and diabetes-related emergencies. Parents, stu-

dents, school personnel, and the diabetes management team work together

to create a safe and supportive environment for school-age children.

INCORPORATING PATIENT EDUCATION

IN CLINICAL PRACTICE

Patient education is essential for management of type 1 diabetes. How-

ever, all medical practice settings are not equipped to provide diabetes

self-management training. Moreover, the complexity of type 1 diabetes, par-

ticularly when treated with intensive therapy, requires health care providers to

have special expertise in diabetes. Physicians who specialize in the treatment

of diabetes and who see many patients with type 1 diabetes can develop a team

relationship with diabetes educators in the community, if hiring educators on

a full- or part-time basis is not feasible. Systems such as health maintenance

organizations, preferred provider organizations, telemedicine, and affiliations

with hospitals offer potential resources for diabetes educators that can work

with a number of physicians to maximize the economy of this specialized type

of care. Physicians practicing in an area where there are education programs

that have achieved American Diabetes Association Recognition may refer

patients to programs that meet the National Standards. The local American

Diabetes Association office maintains a list of recognized programs in their

area, and this list is also available on the Association’s website (www.diabetes

.org/findaprogram).

50 Medical Management of Type 1 Diabetes

To establish a team approach to diabetes self-management education, health

professionals should 1) share a common philosophy toward diabetes manage-

ment and 2) develop efficient methods for communicating about patient care

and education to ensure that a consistent message is given to the patient. Forms,

hand-written or electronic, can be helpful in documenting the educational pro-

cess in a concise format that allows team members to keep abreast of each oth-

ers’ activities and to reinforce all areas of education. Communication by fax and

computers offers the opportunity for expedient transfer of information among

health professionals not working in the same location. Forms, if placed in the

front of a chart or a similar place routinely used in providing patient care, or in

the electronic medical record, can serve as a prompt to educate while providing

routine medical care.

Diabetes education materials can be obtained from the American Diabe-

tes Association, from companies manufacturing pharmaceuticals and diabetes

equipment and supplies, and through a number of additional resources avail-

able through the National Diabetes Information Clearinghouse website at

www.niddk.nih.gov.

CONCLUSION

Patients with type 1 diabetes need self-management education to be able to

implement their treatment regimen. Education should be individualized to reflect

the diabetes treatment regimen and learning characteristics of each patient. Self-

management training is a systematic patient care process that requires educa-

tors with expertise in diabetes and resources of time and materials. Physicians

should use a team approach to manage individuals with type 1 diabetes with

self-management education integrated into the clinical care of the patient.

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Diabetes Standards and Education

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fasting plasma glucose levels with diabetic retinopathy prevalence in the

U.S. population: implications for diabetes diagnostic thresholds. Diabetes

Care 32:2027-2032, 2009

Funnell MM, Brown TL, Childs BP, Haas LB, Hosey GM, Jensen B, Maryniuk

M, Peyrot M, Piette JD, Reader D, Siminerio LM, Weinger K, Weiss MA:

National standards for diabetes self-management education. Diabetes Care

34 (Suppl. 1):S89-S96, 2011

Funnell M, Peyrot M, Rubin RR, Siminerio L: Steering toward a new DAWN

in diabetes management. Diabetes Educ 31 (Suppl.):1-18, 2005

Kanzer-Lewis G: Patient Education: You Can Do It! Alexandria, VA, American

Diabetes Association, 2003

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betes: A Curriculum for Adolescents and Families. Alexandria, VA, American

Diabetes Association, 2001

NDEP: Helping the Student with Diabetes Succeed: A Guide for School Personnel.

Available from www.ndep.nih.gov/media/youth_ndepschoolguide.pdf.

Highlights

Tools of Therapy

INSULIN TREATMENT

basal and prandial (bolus) insulin.

These insulin regimens consist of

n Patients with type 1 diabetes are

• three or more daily injections

dependent on insulin to survive.

(prandial/bolus and basal insulins)

• insulin pump therapy

n The insulins primarily in use

today are: recombinant human

n Insulin needs may fluctuate during

insulin, with the same amino acid

the first weeks or months of treatment.

sequence as native human insulin

If a honeymoon or remission phase

(with or without protamine to delay

occurs, insulin dose must be appropri-

its absorption, onset, and duration)

ately reduced, occasionally to as little

and recombinant human insulin

as 0.1-0.3 units/kg/day, but it should

analogs, in which the amino acid

not be discontinued or replaced with

sequence of human insulin is altered

an oral hypoglycemic agent.

to affect its absorption, onset, and

duration of action.

n Continuous subcutaneous insulin

infusion is an alternative that offers

n Insulin preparations are classified by

advantages in lifestyle flexibility and

duration of action (rapid, short, inter-

glycemic variability.

mediate, and long acting).

n Regimens using insulin algo-

n The insulin regimen should be

rithms place more demands on both

tailored to the needs of the individual

patient and physician than does a

patient. Adjustments in the insulin

fixed course of treatment, but they

regimen or specific insulin doses

provide greater flexibility in lifestyle.

should be based on actual glycemic

All forms of intensive therapy require

values obtained from patient self-

high degrees of long-term commit-

monitoring of blood glucose (SMBG)

ment and flexibility on the part of the

or continuous glucose monitoring

patient, the family, and the diabetes

(CGM) rather than on “textbook”

management team.

predictions of insulin action.

n Common problems associated

n More physiological multiple-

with insulin therapy are detailed in

component “flexible” regimens

Common Problems in Long-Term

emphasize the difference between

Therapy.

TREATMENT WITH THE

• adjustment of insulin, diet, and

AMYLIN ANALOG

physical activity to achieve target

PRAMLINTIDE

blood glucose levels

•

analysis of data (from both SMBG

n Pramlintide is a soluble nonaggre-

and CGM) to look at patterns and

gating amylin analog that is an

trends, daily means (and standard

adjunct to patients receiving prandial

deviations), means (and stan-

insulin therapy. The clinical benefits

dard deviations) by time of day,

of pramlintide are achieved by replac-

and percentages of values in the

ing the action of amylin, a naturally

hypoglycemic and hyperglycemic

occurring b-cell hormone that is defi-

ranges. This can be done by keep-

cient in type 1 diabetes. Results from

ing a log book, or with programs

clinical studies showed that when

that analyze and display the infor-

pramlintide was added to insulin regi-

mation.

mens, patients with type 1 diabetes

had improved glycemic control with

n Four or more SMBG measure-

no increased body weight or severe

ments every day—before breakfast,

hypoglycemia.

lunch, supper, and bedtime—usually

provide the necessary information

sufficient to adjust insulin, activity,

MONITORING

and diet. Tests are done before meals

and at bedtime at a minimum; addi-

n Patients can only manage type

tional testing may be warranted after

1 diabetes effectively and safely if

meals (2 h after the start of the meal);

they self-monitor. This includes self-

in the middle of the night; before,

monitoring of blood glucose (SMBG)

during, and after exercising; on sick

from the finger or an alternate site,

alone or with the additional use of

days; after an intervention to correct a

a continuous subcutaneous glucose

high or low glucose value; or when a

(CGM) sensor, as well as urine or

schedule change has occurred.

blood ketone monitoring as needed

and careful record-keeping.

n Continuous or intermittent glu-

cose monitoring of interstitial fluid is

n Monitoring allows objective goals

available to provide additional infor-

for therapy and a means to measure

mation to adjust insulin, exercise, and

the efficacy of changes in therapy.

diet to optimize glycemic control and

prevent hypoglycemia.

n SMBG is the established monitor-

ing method that allows

n A properly performed A1C

provides the best available index of

• detection and prevention of

chronic glucose levels and is highly

hypoglycemia and hyperglycemia

reliable.

NUTRITION

Supplementation is advised if con-

ditions create a deficiency.

n The overall goal of medical

nutrition therapy (MNT) for type 1

n Insulin therapy regimens using

diabetes is to enable patients to attain

multiple daily doses of insulin allow

blood glucose levels as near normal

greater flexibility in eating patterns

as possible by integrating exogenous

than do conventional regimens.

insulin into their usual eating and

Blood glucose levels obtained by

activity patterns. The MNT prescrip-

self-monitoring can be used to make

tion should be individualized based

adjustments in diet, activity, and insulin

on nutrition assessment and treat-

regimen to maximize blood glucose

ment goals. In general, recommenda-

control.

tions follow nutrition guidelines for

the general population:

n The complexity of integrating

nutrition and insulin therapies and

• Calorie levels should be

the importance of diabetes self-

prescribed to achieve and

management education require a

maintain healthy body weight.

coordinated team approach to care

• Protein intakes of 10-20% of calo-

for individuals with type 1 diabetes.

ries are adequate to support health;

intakes of 0.8-1.0 g/kg/day (~10%

n MNT for diabetes is based on

of daily calories) are recommended

an assessment of the individual’s

for individuals showing evidence

metabolic and lifestyle parameters,

of diabetic nephropathy.

implemented through a nutrition

• Fat consumption should be moder-

self-management plan and evaluated

ate, with saturated fat limited to

through nutrition-related outcomes

<7% of calories, and minimal to no

such as blood glucose and lipid levels

trans fats.

and achievement of a healthy weight

• Carbohydrate foods, such as grains,

and normal growth in children.

Patients and their families should be

dried beans, legumes, vegetables,

fruits, and nonfat dairy products

actively involved in setting nutrition

goals, developing the self-management

are rich sources of vitamins, min-

erals, and/or dietary fiber and are

plan, and evaluating treatment effec-

tiveness through SMBG levels.

preferred choices for carbohydrate-

containing foods. For type 1

n Registered dietitians have the

diabetes, the total amount of car-

bohydrates in a meal, rather than

expertise to design the nutrition

intervention and to counsel patients

the source (sugar or starch), should

guide the estimation of insulin dos-

on nutrition self-management. Nutri-

tional counseling for newly diagnosed

age. The glycemic effect of foods

may provide an additional benefit

patients with type 1 diabetes should

be provided in stages to allow the

to using total carbohydrate.

patient time to adjust to the treat-

• Vitamin and mineral requirements

ment regimen. Nutritional care can-

of individuals with diabetes are the

not be limited to diagnosis but must

same as the general population.

continue throughout the patient’s life

span. Follow-up may be appropriate

• hypoglycemia during or after exer-

every 3-6 months for children and

cise (most likely with sporadic or

every 6-12 months for adults.

inconsistent exercise)

• hyperglycemia and ketosis (if dia-

betes is uncontrolled or ketones

EXERCISE

are present before beginning

activity)

n Exercise should be an integral

part of the treatment plan for patients

n A pre-exercise medical evaluation

with type 1 diabetes.

should be performed regardless of the

patient’s age.

n Physiological responses to exer-

cise in people without diabetes and

n Exercise should be prescribed

in patients with type 1 diabetes are

with caution in patients with

described in Table 3.13. For the type

• unstable blood glucose values

1 diabetes patient, plasma insulin

levels during and after exercise are

• cardiovascular disease, neuropathy

critical determinants of response.

that results in loss of sensation, or

proliferative retinopathy

n Potential benefits of exercise are

• hypoglycemia unawareness

explained on page 123. Some people

do not consider that they exercise,

n Guidelines for safe exercise

but may be physically active because

are addressed in Table 3.17. They

they use stairs, walk their dog, do

include

house cleaning, or gardening. In this

• monitoring blood glucose and tak-

manner, physical activity, like regular

ing appropriate action

exercise, can improve cardiovascular

risk factors and may

• altering food or insulin if needed

• carrying short-acting carbohydrate

• aid in achieving and maintaining a

and identification

healthy weight

• monitoring intensity of exercise

• heighten sense of well-being

• avoiding trauma to joints, muscle,

• improve glucose control

or ligaments as well as to the skin

of the feet

n Potential risks of exercise include

destabilization of metabolic control,

e.g.,

Tools of Therapy

INSULIN TREATMENT

ype 1 diabetes is characterized by a near-absolute deficiency in endog-

enous insulin secretion within days or months after initial diagnosis.

Affected patients are dependent on exogenous insulin to survive for the

duration of their lives, and the insulin regimen must be individualized for each

patient.

INSULIN PREPARATIONS

For the most part, insulin is no longer obtained from animal pancreas but

rather it is made chemically identical to human insulin by recombinant DNA

technology, then either provided in solution (human regular insulin) or com-

plexed with protamine to delay its absorption and duration (human NPH insu-

lin). In addition, there are a number of human insulin analogs, in which the amino

acid sequence of the human insulin molecule has been modified to change its

pharmacokinetics. Insulin preparations are generally classified by duration of

action (rapid-, short-, intermediate-, and long-acting). Three rapid-onset, short-

duration analogs (insulin lispro, insulin aspart, and insulin glulisine) are avail-

able. Human regular insulin and human NPH are characterized as short- and

intermediate-acting, respectively, and two long-acting or basal analogs (insulin

glargine and insulin detemir) are available. Lente (intermediate-acting) and ultra-

lente (long-acting) insulin are no longer available. Other insulin preparations that

may be either more rapid or longer acting are under development. Because there

are many insulin preparations now available, and many more likely to be available

soon, health professionals should familiarize themselves with several preparations

and learn to use them rationally (Tables 3.1 and 3.2).

Species and Purity

In the US today, insulin is prepared by recombinant DNA technology and

no longer derived from animal sources. All insulin preparations sold in the US

are of the highest purity and contain less than one part per million of impurities.

Such purification is associated with a reduced incidence of insulin antibodies, less

insulin allergy, and less lipoatrophy at the injection site than previous less purified

or more immunogenic animal preparations.

Duration of Action

Although insulins are classified into rapid-, short-, intermediate-, and long-

acting preparations, actual insulin effects do not always coincide with such simple

descriptions. For example, local subcutaneous tissue conditions not clearly

understood may cause rates of absorption to vary by 20-40% from day to day

60 Medical Management of Type 1 Diabetes

Table 3.1 Insulins Available in the United States (2012)

Product

Manufacturer

Rapid acting

Humalog (insulin lispro)*

Lilly

NovoLog (insulin aspart)*

Novo Nordisk

Apidra (insulin glulisine)†

sanofi-aventis

Short acting

Humulin R (regular)

Lilly

Novolin R (regular)

Novo Nordisk

Intermediate acting

Humulin N (NPH)†

Lilly

Novolin N (NPH)

Novo Nordisk

Long acting

Lantus (insulin glargine)*

sanofi-aventis

Levemir (insulin detemir)†

Novo Nordisk

Combinations

Humulin 70/30 (70% NPH, 30% regular)†

Lilly

Humalog 75/25 (75% insulin lispro

protamine suspension [NPL], 25% insulin lispro)†

Lilly

Humalog 50/50 (50% NPL, 50% lispro)†

Lilly

Novolin 70/30 (70% NPH, 30% regular)

Novo Nordisk

Novolog 70/30 (70% insulin aspart protamine,

30% insulin aspart)

Novo Nordisk

*Available in prefilled disposable pen injectors and cartridges for pen injectors in addition to vials.

†Available in cartridges for pen injectors in addition to vials.

in any one patient. In light of the many other variables influencing insulin phar-

macokinetics, the clinician is cautioned against relying too heavily on textbook

descriptions of insulin action. Health professionals should base therapy adjust-

ments on actual glycemic values obtained from the patient’s self-monitoring of

blood glucose (SMBG) or CGM.

Rapid- and short-acting insulins are relatively predictable on a day-to-day

basis in onset and duration of action. Therefore, they can be adjusted after a

2- to 3-day observation period to attempt to normalize postprandial glucose

values. This adjustment can be made by changing a fixed dose or the insulin-

to-carbohydrate ratio or the timing of insulin in relation to the meal or the

amount of insulin used to correct a glucose value above the target range (cor-

rection algorithm). Any change in the dose of intermediate-acting (NPH) or

long-acting (glargine or detemir) insulin requires a 2- to 5-day observation

period before further dose adjustment because of the relatively slow absorp-

tion and long duration of action of these insulins and because of day-to-day

variability in food, activity, and stress.

The use of SMBG to map out a profile of blood glucose values is invaluable

in assisting the physician, patient, and diabetes management team with therapy.

Blood glucose levels should be measured before and after meals and during the

Tools of Therapy

Table 3.2 Insulins by Comparative Action

Onset (h)

Peak (h)

Effective duration (h)

Rapid acting

Insulin lispro (analog)

<0.25-0.5

0.5-2.5

3-6.5

Insulin aspart (analog)

<0.25

0.5-1.0

3-5

Insulin glulisine (analog)

<0.25

1-1.5

3-5

Short acting

Regular (soluble)

0.5-1

2-3

3-6

Intermediate acting

NPH (isophane)

2-4

4-10

10-16

Long acting

Insulin glargine (analog)

2-4

Relatively flat

20-24

Insulin detemir (analog)

0.8-2

Relatively flat

Dose dependent

(dose

12 h for 0.2 U/kg;

dependent)

20 h for 0.4 U/kg;

up to 24 h.

binds to albumin.

Combinations

70% NPH, 30% regular

0.5-1

Dual

10-16

75% NPL, 25% lispro

<0.25

Dual

10-16

50% NPL, 50% lispro

<0.25

Dual

10-16

70% aspart protamine,

30%aspart

<0.25

Dual

15-18

night, particularly when initiating or intensifying insulin therapy or when seeking

the cause of hypoglycemia or hyperglycemia. CGM may be a helpful tool because

of the increase in number of glucose values obtained each day. Routine frequency

of monitoring or use of CGM should be based on mutually defined goals described

in Philosophy and Goals.

Insulin Pens and Apps

Most of the current human insulins and insulin analogs are available in insu-

lin cartridges and/or disposable pens (Table 3.1). Such devices aid the patient

in insulin measurement and simplify insulin administration with minimal added

cost to therapy. Several manufacturers of insulin pens and pen needles exist; pens

are either durable or disposable, and some devices deliver insulin by half units or

have a memory device that records the prior doses. Use of pen devices, will not

only facilitate the adaptation to basal-bolus therapy, and enhance the compliance

to intensive insulin therapy but also improve outcomes when using flexible regi-

mens. A cover to the pen has just been developed and released that keeps track of

the last dose of insulin given. Applications on glucose meters and via the Internet

on phones or computers can be used to record insulin doses as well.

62 Medical Management of Type 1 Diabetes

Mixing Insulins

Mixing insulin is declining in the US because fixed regimens are being

replaced by flexible basal-bolus regimens and pen usage is increasing. Insulin

glargine and insulin detemir should not be mixed with other insulins. Mixing

short- or rapid-acting insulin with NPH in the same syringe is an accepted and

convenient way to produce differently timed pharmacologic actions with a single

injection. Stable premixtures of intermediate- and short- or rapid-acting insulins

in fixed proportion (e.g., 70% NPH/30% regular, 75% NPL/25% insulin lispro,

50% NPL/50% insulin lispro, and 70% NPA/30% insulin aspart) are also avail-

able commercially. Premixed insulins are not suitable when daily variation in the

dose of short-acting insulin is required, which is the case for most patients with

type 1 diabetes.

TREATING NEWLY DIAGNOSED PATIENTS

Diagnosis and Stabilization

At diagnosis, initial objectives of therapy are dependent on the degree of ill-

ness (e.g., resolving DKA if it exists, eliminating symptomatic hyperglycemia,

or initiating insulin therapy in the asymptomatic patient). The goal is to resolve

hyperglycemia, fluid deficit, and electrolyte disturbance while avoiding hypogly-

cemia. Therefore, glycemic targets should be approached gradually. Treatment

should begin with ~0.6-0.75 units of insulin per kg body weight per day. How-

ever, during the first week of ŧherapy, this amount can be expected to increase

to an average of 1.0-1.5 unit/kg/day, because most patients are relatively insulin

resistant at this time. This is particularly true for adolescents and those who pres-

ent in DKA.

Immediately after diagnosis or after ketoacidosis has been resolved, therapy

should begin with the insulin program that is negotiated and agreed upon between

the patient/family and health care team, e.g., two or three daily insulin injections

or a “flexible” intensive insulin program consisting of preprandial or bolus insu-

lin at each meal and basal insulin once or twice per day. It is preferable to start

with the flexible basal-bolus insulin program at the outset instead of learning

twice-daily insulin injections, a therapy that eventually fails. Although twice- or

once-daily insulin may suffice for a short time in patients who retain some of their

b-cell function, psychological acceptance of flexible intensive injection programs

is easier for both patient and family if introduced as soon as possible after diagno-

sis, even if glycemic control could be adequate on a different program with fewer

injections. Moreover, there is evidence from the Diabetes Control and Complica-

tions Trial (DCCT) and EDIC that intensive exogenous insulin helps preserve

b-cell function and should be given in adequate doses so that the patient does not

need to utilize endogenous insulin for routine glycemic control.

Although not recommended, some clinicians start with two or three insulin

injections per day, to acquaint the patient with basic diabetes management prin-

ciples, before initiating a flexible intensive program. With the two-dose regimen,

about two-thirds of the insulin dose is given in the morning before breakfast, and

Tools of Therapy

one-third is given before supper. The two doses may consist of premixed insu-

lins (sometimes the case for infants and very young children) or two doses of a

mixture of rapid- or short- and intermediate-acting or long-acting insulins. The

prebreakfast dose consists of about two-thirds NPH and one-third regular or

insulin aspart or lispro. The presupper dose is usually divided into equal amounts

of NPH or insulin glargine or detemir, and regular insulin or insulin aspart, lis-

pro, or glulisine. For the three shot regimen, the same is followed, however, the

evening doses are split with the regular insulin or rapid-acting insulin before din-

ner and the NPH or insulin glargine or detemir before bed.

Patients and families should be taught the technique of blood glucose moni-

toring at diagnosis. They should determine blood glucose levels repeatedly under

professional supervision to ensure the reliability of the readings. If premixed for-

mulations (e.g., 70% NPH/30% regular; 75% NPL/25% insulin lispro) are used

initially, patients should have supplies of short- or rapid-acting insulins for use

when needed, such as supplementation for sick days.

Remission or Honeymoon Phase

Within weeks after diagnosis, with resolution of ketosis and hyperglycemia,

there may be some recovery of b-cell function, and consequently, exogenous

insulin requirements often decrease for weeks to months. This honeymoon phase

of type 1 diabetes may be marked by the appearance of recurrent hypoglycemic

reactions. A honeymoon phase occurs less frequently in younger children; it is

more common in the late teenage years and in adults. During this period, insulin

dosage must be appropriately reduced, occasionally to as little as 0.1-0.3 units/

kg/day. Not all patients exhibit a profound honeymoon phase, but some period of

stability in blood glucose levels is common, with insulin requirements at 0.2-0.5

units/kg/day. Evidence suggests that the honeymoon phase could be prolonged if

blood glucose levels are kept in the near-normal range with basal/bolus therapy.

There should not be an attempt to reduce insulin to the lowest dose possible nor

to discontinue insulin, because of the apparent benefits of even modest preserva-

tion of b-cell function. Instead, the patient should receive the highest dose that

does not induce hypoglycemia.

The TrialNet Study, a large multinational trial in the US, Canada, Australia,

and Europe, has one of its goals to preserve b-cells, as assessed by C-peptide

secretion, at the onset of type 1 diabetes. This study is investigating the use of

immune-suppressive and immune-modulating agents, as well as intensive meta-

bolic control. Patients should be informed of this study at the time of diagnosis.

Patients and families can be referred to the TrialNet website www2.diabetestri-

alnet.org, to determine whether they are interested and eligible for any studies.

Chronic Phase: Developing a Long-Term Treatment Plan

As the honeymoon period comes to an end with the progressive decrease

of b-cell function, insulin requirements increase gradually over several months.

Prepubertal children and adults usually require between 0.6 and 0.9 units/kg/day,

and pubertal children may require up to 1.5 units/kg/day because of relative insu-

lin resistance, increased caloric intake during rapid growth spurts, and changes in

64 Medical Management of Type 1 Diabetes

hormone secretory patterns. After puberty, insulin doses should decrease to <1.0

units/kg/day to prevent excessive weight gain. Dose requirements for pregnant

patients vary with gestational duration and are discussed in Pregnancy (page 161).

Careful balance of caloric and carbohydrate intake, activity, and insulin dose

is required for an insulin regimen to be successful. It is most desirable to vary

insulin doses to coincide with variations of food intake, activity, and prevailing

blood glucose. On the other hand, if insulin dose is kept constant from day to

day, food intake and activity should also be kept constant. The choice of insulin

regimen should be based on individual characteristics, preferences, and habits,

including age, stage of development, meal plans, and potential adherence to dia-

betes treatment. The diabetes management team should develop an acceptable

and realistic treatment plan together with the patient/family. For example, an

adolescent patient who is experiencing difficulties in following the treatment and

has frequent episodes of hyperglycemia or ketoacidosis may have to be treated

with two injections per day administered by a family member or visiting nurse

until his or her problems are resolved. School can be used to administer one of

the injections. On the other hand, the choice of insulin regimen should not be

dictated by forces outside of the patient/family and health care team. For school-

age children, the school must accommodate the delivery of a lunchtime injec-

tion of insulin if the child/family and health care team decide to use an intensive

insulin regimen. Employed adults should similarly have flexibility for testing and

injecting in the workplace.

After the initial dose adjustments, ongoing long-term adjustments are made

on the basis of daily repeated blood glucose measurements or the use of CGM.

Glucose levels should be assessed before meals, after meals, and at bedtime every

day and periodically between 3:00 and 4:00 a.m. (perhaps once per week). With

time and practice, patients and families are able to make the adjustments with

relative ease and become progressively independent of the diabetes management

team. This includes determining how to adjust the carbohydrate-to-insulin ratio

and the insulin sensitivity factor used to calculate the amount of insulin needed

to correct a glucose level above the target range. In addition to the long-term

adjustments, insulin doses and waiting times between injections and food intake

could be adjusted in response to high or low blood glucose levels, changes in

food intake, activity level, or intercurrent illness. These adjustments can be made

by patients who have been thoroughly trained and who can measure their blood

glucose levels or use CGM and calculate dose changes precisely.

Patient education is time-consuming but essential and should be conducted

by a skilled diabetes management team working together with the patient and

his or her family. Many newly diagnosed patients will require an initial period of

instruction of up to 10-12 h, with periodic review and follow-up sessions every

few months until both patient and family feel comfortable with their knowledge

and skills. Insulin regimens and blood glucose targets also should vary depending

on the individual patient and should take into consideration the frequency and

adherence to SMBG or CGM, the patient’s ability to recognize and respond to

hypoglycemic reactions, and the limitations imposed by what the patient and/or

family are willing or ready to do. However, individualization should not prevent

continued efforts toward the goal of achieving near-normoglycemia while avoid-

ing severe hypoglycemia.

Tools of Therapy

A frequent problem in the management of diabetes is the disappointment

that sets in at the end of the honeymoon period when patients with or parents

of children with type 1 diabetes realize that the efforts invested in the treatment

are not rewarded by the achievement of normoglycemia. Often, minor deviations

from treatment or even no deviations at all result in unexplained fluctuations of

glucose levels. Because these fluctuations are part of the nature of type 1 diabetes,

even under the strictest and most flexible treatment conditions, such as with the

use of multiple injections and insulin pumps, it is helpful at diagnosis to warn

patients and families that the treatment of diabetes is imperfect and that glucose

fluctuations are to be expected. Adequate explanations about the unpredictabil-

ity of blood glucose levels and their relationship to daily variations of insulin

absorption, food composition and absorption, and changes in the level of physical

activity often help to prevent the development of feelings of guilt and incompe-

tence that can plague patients and families. A useful attitude on the part of the

diabetes management team is to stress the importance of overall blood glucose

control, such as assessing the mean glucose from meter or CGM readings, rather

than individual values. However, if individual values are used, relatively wide

flucŧuations (70-160 mg/dL [3.9-8.9 mmol/L] preprandial, up to 200 mg/dL

[11.1 mmol/L] postprandial, and between 90 and 200 mg/dL at bedtime and

overnight [5.0-11.1 mmol/L]) can be suggested, even when narrower glycemic

targets might be preferred.

INSULIN REGIMENS

General Principles

Normal insulin secretion is characterized by continuous basal release, with

superimposed bursts of additional insulin integrated precisely to the rise in glu-

cose after food intake. Additionally, insulin is secreted into the portal vein and

approximately half is cleared by the liver before entering the general circulation.

Ideally, exogenous insulin treatment regimens should mimic all aspects of this

pattern. Unfortunately, with the available means of treatment, this is not entirely

possible. Therefore, insulin treatment regimens represent varying degrees of

compromise to achieve near-normalization of blood glucose levels, one of the

most important goals of diabetes management. Ideally, insulin regimens should

have both basal and bolus components to mimic normal insulin secretion.

The normal prandial burst of insulin is best mimicked by administering rapid-

acting (insulin lispro, aspart, or glulisine) or short-acting (regular) insulin before

meals at the appropriate time, depending on the blood glucose level. Prandial

insulin typically comprises ~50-60% of the total daily dose. Advantages of rapid-

acting insulin analogs over human regular insulin are convenience (injection

before, at the time of or immediately after a meal instead of 30 min premeal), better

postprandial control, and reduced risk of postprandial hypoglycemia occurring

3-6 h postinjection. Disadvantages of rapid-acting analogs are cost and inability

to cover snacks without another bolus dose of insulin.

Basal insulin secretion comprises ~40-50% of the total daily insulin secre-

tion. It can be mimicked best by giving long-acting insulin glargine or detemir

66 Medical Management of Type 1 Diabetes

once or twice a day or by delivering short- or rapid-acting insulin continuously

by an insulin pump (continuous subcutaneous insulin infusion [CSII]). The basal

insulin in CSII has the advantage of being variable and adjustable to cover the

early morning rise in glucose levels (the dawn phenomenon) as well as periods of

increased insulin sensitivity such as nighttime or during or after exercise. Com-

pared to NPH, insulin glargine and detemir have the advantage of being rela-

tively peakless. Insulin glargine has an onset of action of 1.5 h postinjection and

mean duration of action being 23.5 h after several days of injections. As a result,

clinical studies in type 1 diabetes have shown better fasting blood glucose with

less nocturnal hypoglycemia than NPH once, twice, or four times daily. In ~20%

of individuals, glargine lasts <20 h and may have to be given twice daily, usually

in a 50:50 format. Insulin detemir achieves its longer duration by binding insulin

with albumin and is injected once or twice daily. It has an onset of action between

0.8-2 h and a duration that is dose dependent lasting ~12 h at 0.2 units/kg and

~20-24 h at 0.4 units/kg. Disadvantages of glargine and detemir over NPH are

that they are only basal insulins and do not cover snacks without a bolus injec-

tion, they cannot be mixed with other insulins in the same syringe, and they are

more costly.

NPH can be used as a basal insulin and should be given twice daily at breakfast

and bedtime. NPH has an onset of action ~2 h after the injection and produces

peak levels ~6-10 h after injection. Morning NPH provides hyperinsulinemia,

especially in mid- or late afternoon, when snacks may be needed to prevent hypo-

glycemia. Bedtime NPH provides progressive overnight basal hyperinsulinemia

with peak serum insulins around breakfast time; giving the injection at bedtime

rather than pre-supper reduces the risk of nocturnal hypoglycemia and may pro-

vide coverage for the dawn phenomenon. Long-acting insulin is given once daily

before breakfast or at bedtime or twice daily at breakfast and bedtime or at break-

fast and supper.

Starting Insulin Requirement

The starting insulin dose is usually based on body weight. On average, a

patient will eventually require anywhere between 0.4 to 1.0 units/kg/day with

higher amounts during puberty. It is best to start conservatively at 0.5 units/kg/

day and increase insulin doses according to SMBG readings.

Two or Three Injections Daily

The twice-daily “split-mixed” insulin regimen (Fig. 3.1) was the most com-

monly used treatment regimen before results of the DCCT. Morning short- or

rapid-acting insulin (regular or insulin aspart/lispro/glulisine) has major action

between breakfast and lunch, and its effect is reflected in the prelunch blood

glucose levels. Morning intermediate-acting (NPH) insulin has major action

between breakfast and supper, and its effect is reflected in the presupper blood

glucose levels. Evening short-acting insulin has major action between supper and

bedtime, and its effect is reflected in the bedtime tests. The evening intermediate-

acting insulin has its major action overnight, and its effect is reflected in the blood

glucose level on arising the next morning. The evening intermediate-acting

Tools of Therapy

insulin can be replaced with long-acting insulin. The initial dose can be divided

(based on % of total daily insulin) into a morning injection containing ~40%

NPH and ~15% insulin aspart/lispro/glulisine or regular at breakfast, plus an

evening injection containing ~30% NPH (or long-acting insulin) and ~15% insu-

lin aspart/lispro/glulisine or regular at supper. In younger children, the propor-

tions are closer to 80%/20% for both components.

The only advantages to this regimen are simplicity and a limited number of

injections. The most frequent and serious disadvantage of this regimen is that,

in many patients, attempts to achieve fasting normoglycemia result in nocturnal

hypoglycemia (from midnight to 4:00 a.m.) and early morning hyperglycemia

(from 4:00 to 8:00 a.m., due to the dawn phenomenon). In these cases, it is bet-

ter to move the intermediate-acting insulin to bedtime and thus reduce the peak

effect of insulin from 2:00 to 4:00 a.m. and increase it at dawn (Fig. 3.1B). In

addition, post lunch hyperglycemia is often not controlled without the risk of

daytime hypoglycemia from ratcheting up the morning NPH dose, and thus, an

insulin injection at lunch or with an afternoon snack is often needed. Generally,

it is not possible to achieve near-normal glycemic levels with two or three injec-

tions per day.

Multiple-Component Flexible Regimens

Basal insulin requirements typically account for ~50% (less in children and

teens, closer to 35-45%) of the patient’s total daily dose. Basal insulin may be

provided as glargine, detemir, or NPH insulin or as a rapid-acting insulin with

multiple-dose insulin programs or as a basal infusion of insulin analog with

CSII (regular insulin is infrequently used in insulin pump therapy) (Fig. 3.2).

The remaining ~50% (more in children and teens, closer to 55-65%) is given

as prandial insulin, using a rapid-acting insulin analog delivered before meals

and/or snacks either by syringe, pen, or an insulin pump bolus. Short-acting

regular insulin is less frequently used in multiple-component flexible regimens.

The amount of prandial insulin can be determined by calculating the insulin-to-

carbohydrate ratio (discussed below) or by using a typical starting distribution

of ~25% of the total daily dose as a rapid-acting insulin pulse before breakfast,

~10% before lunch, and ~20% before supper. These prandial boluses are varied

based on the carbohydrate content of the meal as well as the actual blood glucose

determined by SMBG at that time.

Glargine and detemir cannot be mixed in the same syringe with other insulin

preparations. Another alternative is the combination of premeal injections (regular

insulin or rapid-acting insulin analogs at breakfast, lunch, and supper, with NPH at

bedtime; or with a small amount of NPH before breakfast (Fig. 3.3) or at every meal.

The combination of premeal rapid-acting insulin analogs with long-acting

basal insulin (glargine or detemir) every 12 or 24 h is quite popular because, 1)

it offers flexibility in meal size and timing, 2) it is very easily understood by most

patients because each period of the day has a well-defined insulin component, 3)

the pharmacokinetics of analogs more closely mimics normal basal and prandial

insulin secretion, and 4) the introduction of insulin pens has made it very con-

venient. Bedtime administration of glargine or detemir allows the easy titration

68 Medical Management of Type 1 Diabetes

of the fasting glucose to normal with minimal risk of nocturnal hypoglycemia.

If bedtime or presupper glucose levels are high with normal postlunch values

and no afternoon snack, then consider the use of glargine twice a day. Another

basal option is basal insulin only in the morning with titration to obtain the fast-

ing morning glucose levels to be in the normal range. If this is not successful

due either to daytime hypoglycemia or fasting hyperglycemia, then basal insulin

should be given twice a day.

Continuous Subcutaneous Insulin Infusion (CSII)

The most precise way to mimic normal insulin secretion clinically is to use

an insulin pump in a program of CSII. Pump devices provide continuous insu-

lin administration to control blood glucose levels throughout the 24-h period.

Because insulin delivery is continuous, it can more or less mimic normal insulin

secretion. The pump delivers microliter amounts (as low as 0.025 units) of rapid-

acting insulin on a continual basis, thus replicating basal insulin secretion (short

acting insulin is rarely used in CSII). The basal rate may be programmed to vary

at times of diurnal variation in insulin sensitivity. For example, the basal infusion

rate may be programmed to decrease at night to avert nocturnal hypoglycemia

and/or to increase in the early morning to counteract the dawn phenomenon.

More than one basal pattern can be set if there are marked variations in insulin

needs on different days (such as differences in activity levels between the week-

days and weekends, or for teenaged girls and women who experience a change

in insulin requirements at different times in their menstrual cycle). Unique pat-

terns of basal infusions may be needed by some patients, but most patients’ circa-

dian insulin requirements are met with two to four basal rates per day.

The pump is activated before meals to provide increments of insulin as meal

“boluses” whenever a meal or snack is consumed. This allows total flexibility in

meal timing. Meal boluses with rapid-acting insulin analogs are given 10-20 min

before eating a meal. For small children with erratic eating patterns, the meal

bolus may be delivered immediately after the meal when the amount of food

consumed is known. A similar strategy can be used for the patient who is anorexic

or nauseated (e.g., in early pregnancy or during illness). If a meal is skipped,

the insulin bolus is omitted. If a meal is larger or smaller than usual, a larger or

smaller insulin bolus is selected based on the carbohydrate content of the meal.

Some pumps also offer variable bolus options including immediate delivery,

square-wave delivery over a set amount of time (~2 h), or dual-wave delivery with

both immediate and square-wave delivery together. Dual-wave delivery is use-

ful for high-fat meals such as pizza and Mexican food, as well as for patients

suspected of having gastroparesis. Frequent SMBG or the use of a continuous

glucose monitor will help to determine the proper setting of the immediate and

square-wave bolus. Thus, CSII patients have the potential of easily varying meal

size, content, and timing, as well as omitting meals.

The ability to program insulin pumps also allows “suspension” of insu-

lin delivery with increased physical activity, which serves to reduce the risk of

exercise-related hypoglycemia. Caution should be taken regarding the duration

of suspension of the basal insulin delivery because hyperglycemia and ketosis

may rapidly supervene if insulin delivery is interrupted for >2 h. Switching to a

reduced temporary basal for a set amount of time may be preferable.

Tools of Therapy

Morning Afternoon Evening Night

Rapid

NPH

Meals

Morning Afternoon Evening Night

Rapid

NPH

Meals

Figure 3.1 Schematic representation of idealized insulin effect provided by

(A) “split-mixed” insulin regimen consisting of two daily injections of rapid-

and intermediate-acting insulin given before breakfast and supper and

(B) three daily injections with rapid- and intermediate-acting insulin before

breakfast, rapid-acting insulin at supper, and intermediate-acting insulin

at bedtime. B, breakfast; L, lunch; S, supper; HS, bedtime; Arrow, time of

insulin injection, before meals.

Infusion pumps are relatively small, lightweight, portable, battery-driven

devices; they are either attached directly to the body (patch pump) or worn on

clothing or in a pouch (traditional pump). The patch pump is placed on the skin

with adhesive and the small needle catheter is automatically inserted under the

skin; after insertion they cannot be removed temporarily. The patch pump is

controlled by a handheld personal digital assistant (PDA). The traditional pump

is attached via plastic tubing to a small subcutaneous catheter that is taped to the

70 Medical Management of Type 1 Diabetes

Rapid Rapid

Rapid

Glargine (G) / Detemir (D)

(G or D)

(D)

Meals

Figure 3.2 Schematic representation of idealized insulin effect provided

by three daily injections with rapid-acting insulin at meals and once-daily

insulin glargine or detemir at bedtime. Detemir sometimes is given twice

daily (dashed arrow). B, breakfast; L, lunch; S, supper; HS, bedtime; Arrow,

time of insulin injection.

skin; most of these catheters offer a quick-release device to remove the pump for

such activities as swimming, contact sports, showering, sexual activity, or dress-

ing. The devices on the market have such features as alarms for low battery,

blocked delivery, and empty reservoir. Other options found in pumps include

calculating meal or correction boluses based on insulin-to-carbohydrate ratio

algorithms and insulin sensitivity factors, setting glucose targets, determining the

amount of active insulin so as to avert hypoglycemia when giving multiple correc-

tion doses, alerting to recommend SMBG tests and changing the infusion sets at

specified times, and wireless connections to blood glucose meters. Insulin pumps

can be integrated with continuous glucose monitors. The information from the

pump or PDA memory can be extracted for review of total daily insulin doses,

number and timing of insulin boluses, carbohydrate intake used in bolus calcula-

tions, pump settings, and glucose levels from SMBG or CGM by the patient,

family, and the health care team.

Treatment with insulin pumps is extremely effective in improving glucose

control in patients with type 1 diabetes, particularly those motivated patients most

interested in meticulous glycemic control. As long- and rapid-acting insulin ana-

logs have been developed, however, multiple-dose insulin regimens have become

increasingly comparable to pump therapy in terms of the ability to mimic normal

physiology. However, the results of a meta-analysis of 12 randomized controlled

trials comparing pumps to optimized MDI showed less insulin is used and glycemic

control is better during pump therapy. Although the difference is small, it should be

sufficient to reduce risk of microvascular disease. Disadvantages of pump therapy

include cost and the need to overcome the psychological aversion some patients

Tools of Therapy

Morning Afternoon Evening Night

Rapid Rapid

Rapid

NPH

Meals

Figure 3.3 Schematic representation of idealized insulin effect provided by

three daily injections with rapid-acting insulin at meals and two daily injections

of intermediate-acting insulin at breakfast and at bedtime. B, breakfast; L,

lunch; S, supper; HS, bedtime; Arrow, time of insulin injection.

have to “always being hooked to something.” In addition, due to the short dura-

tion of rapid-acting analogs and the lack of a subcutaneous depot of basal insulin,

patients on pump therapy can develop severe hyperglycemia or ketosis rapidly with

interruption of insulin delivery (such as kinking or disconnection of the subcutane-

ous cannula, empty insulin reservoir, or pump malfunction). Such episodes can be

prevented or averted quickly with proper attention and education. Indications for

CSII are listed in Table 3.3.

On initiating CSII therapy, the patient must receive instruction from the dia-

betes management team, including

n accurate monitoring of capillary blood glucose before each meal, after

each meal, at bedtime, and at mid-sleep

n knowing safe blood glucose targets during the day and night and the

duration of active insulin to avoid hypoglycemia, the most frequent

complication of intensive therapy

n learning strategies to reduce the risk of nocturnal hypoglycemia, if it

ensues, including increasing the target fasting blood glucose to

100-140 mg/dL (5.6-7.8 mmol/L), decreasing the basal rate if 3:00

a.m. blood glucose levels are <80 mg/dL (<4.4 mmol/L), and daily

measurements of blood glucose levels at bedtime followed by ingestion

of carbohydrate (or carbohydrate in combination with protein and/or

fat) or use of temporary basal rates if the values are ≤100 mg/dL

(≤5.5 mmol/L)

n understanding how to avoid hypoglycemia during and after exercise by

suspending or decreasing basal insulin infusion and/or ingesting addi-

tional carbohydrate

72 Medical Management of Type 1 Diabetes

CSII with Rapid Analog

Figure 3.4 Schematic representation of idealized insulin effect provided by

continuous subcutaneous insulin infusion (insulin pump) with rapid analog.

B, breakfast; L, lunch; S, supper; HS, bedtime. Arrow, time of insulin bolus,

at meals.

n caring for infusion site with changes of the catheter every 2-3 days to

avoid infection and inflammation

n understanding the urgency of preventing or reversing hyperglycemic

crises from insulin underdelivery by taking the following steps with detec-

tion of moderate unexplained hyperglycemia: monitoring urine or blood

ketones, changing the infusion set or taking an insulin injection immedi-

ately, contacting the medical team for persistent problems, and trouble-

shooting the reasons for insulin underdelivery (crimped cannula, leaking,

obstruction, pump failure) after correcting the hyperglycemia

n knowing how to contact experienced medical personnel by phone

24 hours per day, 7 days per week

n having the constant presence of a relative or friend until the patient

becomes familiar with the pump

The initial programming of the pump is based on the total daily insulin dose

of the previous regimen. Approximately 35-50% of the total dose is given as the

basal rate, and the rest is divided between breakfast, lunch, supper, and snacks.

For insulin-to-carbohydrate ratio, divide 450 by the average total daily insulin

dosage, and for insulin sensitivity factor, divide 1700 (or 1500 if more insulin

resistant) by the average total daily insulin dosage. The patient is generally started

with a single basal rate over a 24-h period. Bedtime snacks are not given until the

basal rate is correct overnight. The basal rate is adjusted every second or third day

on the basis of the blood glucose levels at bedtime, mid-sleep, and on rising until

the desired blood glucose target is obtained. Increments should be in the order of

10-15% or 0.1 units/h (or 0.025-0.05 units/h for young children). In the case of

nocturnal hypoglycemia, basal rate should be lowered starting 2-3 h before the

Tools of Therapy

Table 3.3 Indications for Insulin Pump Therapy (CSII)

n Inadequate glycemic control, defined as:

n History of severe hypoglycemia or hypo-

u A1C above target (>7.0% nonpregnant,

glycemia unawareness

>6.5% if planning pregnancy, >6.0% if

n Desire for flexibility in lifestyle (e.g., shift

pregnant)

worker, traveler, or worker in safety-

u Dawn phenomenon with fasting glu-

sensitive job, student, erratic schedule

cose >140 mg/dL (>8 mmol/L)

day to day)

u Marked variability in glucose levels on

a day-to-day basis

n Commitment to frequent SMBG or CGM

and skilled in intensive diabetes

management

time of the hypoglycemic event. Patients exhibiting the dawn phenomenon may

require increased basal rates in the early morning hours starting 2-3 h before

waking and lasting 4-6 h. Children may have a reverse dawn phenomenon requir-

ing higher basal rates between 10:00 p.m. and 2:00 a.m. Basal rates are adjusted

during the day by delaying meals to determine if the blood glucose levels rise or

fall >30 mg/dL (>1.7 mmol/L) during that time. Daytime basal rates for those

on rapid-acting analogs can often be determined by observing late postprandial

glucose patterns (for example, pre-lunch and pre-supper glucose levels, when the

effects of the prior meal bolus are no longer in effect) or by skipping a meal and

seeing the effect of basal rates alone.

Even when a patient’s initial commitment persists, the use of pumps may be

associated with various problems. These include local inflammation at catheter

sites from infection or tape irritation, pump breakdown and/or malfunction, for-

getting to refill reservoirs on time, or forgetting to give meal boluses. Appropri-

ate education in troubleshooting hyperglycemia, hypoglycemia, as well as other

problems must be provided. Many of the problems with CSII of the past have

been solved; there is less local irritation at insertion sites and less insulin pre-

cipitation, there are more programmable features to calculate bolus doses and

duration of active insulin, and more alerts, and pump therapy can be combined

with CGM. As a result, pump therapy continues to increase in patients of all

ages. Once initiated, most patients remain on CSII, and although there are no

large-scale randomized trials, except for sensor augmented pump studies, clinical

reports and experience suggest that patients (including toddlers and young children)

have improved glycemic control, less hypoglycemia, and improved quality of life.

Insulin pumps coupled with CGM and control algorithms are now able to

have automation of some aspects of insulin delivery. For example, insulin deliv-

ery can be suspended automatically after a pre-set glycemic threshold has been

reached, referred to as the “low glucose suspend” feature. This feature appears to

be able to reduce time spent in hypoglycemia without increasing hyperglycemia.

Predictive algorithms are being evaluated that will suspend insulin prior to reach-

ing the threshold to prevent, not just reduce, hypoglycemia. These automated

steps are part of the “artificial pancreas” that someday may allow for the full

automation of insulin delivery.

74 Medical Management of Type 1 Diabetes

ALTERNATIVE INSULIN DELIVERY SYSTEMS

Multiple alternative methods for delivering insulin into the bloodstream have

either been developed or are under development and investigation. These include

pulmonary insulin delivered through inhalation, peritoneal insulin delivered via

implantable pumps, and transdermal and buccal insulin delivery.

Pulmonary delivery of insulin in humans was initially reported in 1925, with fur-

ther studies in the 1970s and 1980s confirming the feasibility of administering insulin

by the aerosol route. In these studies, ~10-30% of the insulin inhaled was absorbed

into the circulation and the aerosols appeared to be well tolerated. The first pulmo-

nary insulin preparation was approved by the FDA in January 2006, but was subse-

quently removed from the market by the manufacturer in late 2007 for financial/

business reasons. However, many other preparations remain under development.

Studies in patients with type 1 or type 2 diabetes have shown that inhaled

insulin is absorbed more rapidly than subcutaneous regular insulin and as quickly

or quicker than rapid-acting insulin (aspart/lispro). The bioavailability of inhaled

insulin relative to subcutaneous regular insulin is ~10% with all the current

inhaled systems in development except for technosphere insulin, which has ~30%

bioavailability. The intrasubject variability of inhaled insulin is comparable to sub-

cutaneous regular insulin. Studies in smokers and chronic obstructive pulmonary

disease patients have shown enhanced absorption of inhaled insulin, with studies

in asthma patients showing some decreased absorption.

Results of studies in patients with rhinovirus infection have been mixed, with

most showing no substantial change in the pharmacokinetics of inhaled insulin.

Results from studies of the use of inhaled pulmonary insulin have shown that they

are as effective as subcutaneous insulin regimens in type 1 and type 2 diabetes

patients. Quality of life and treatment satisfaction assessments have shown inhaled

insulin therapy is preferred over subcutaneous insulin therapy by many patients.

The most frequently reported adverse event is hypoglycemia. Mild changes in

pulmonary function have been reported but have been felt to be reversible and of

little clinical significance.

Continuous peritoneal insulin infusions via programmable implantable insulin

pumps have been used for over 20 years, although only in research settings in

the US. Intraperitoneal insulin is rapidly and predictably absorbed into the portal

circulation, simulating physiologic insulin delivery and absorption. Such rapid and

predictable absorption may avoid the peripheral hyperinsulinemia seen with sub-

cutaneous insulin regimens and the theoretical risk of accelerated atherosclerosis.

Clinical studies have proven implantable pump therapy to be safe and effective for

achieving glycemic control (significant reductions in A1C, average glucose level,

and glucose variability), decreasing the rate of severe hypoglycemia, and improv-

ing glucagon responses to hypoglycemia.

OPTIMIZING BLOOD GLUCOSE CONTROL

Physiologic insulin secretion in nondiabetic individuals involves 1) meal-

related increased insulin secretion initiated by neural and gut factors before

the hyperglycemic stimulus that is responsible for tissue uptake and storage of

nutrients, followed by a rapid return of insulin secretion to the baseline level,

Tools of Therapy

and 2) basal insulin secretion between meals and during the night to regulate

amino acids and fatty acids in the fasting state and to prevent excessive fasting

gluconeogenesis. It is presumed that only an artificial or bioengineered b-cell

with continuous glucose monitoring and the administration of short-acting insu-

lin into the portal circulation can replicate the function of the normal pancreas.

Proper diabetes management has the goal of approaching normal blood

glucose levels without severe hypoglycemia. The preprandial plasma blood glu-

cose levels will most likely be outside the desired premeal values of 90-130

mg/dL (5.0-7.2 mmol/L) and peak postprandial values of <180 mg/dL (<10.0

mmol/L). Safe middle-of-the-night values are in the range of 70-120 mg/dL

(3.9-6.7 mmol/L). These targets are difficult to maintain safely except under very

intensive programs with selected patients, although use of CGM has been shown

to reduce hyperglycemia by 30%.

The implications of the DCCT findings are that optimal treatment should be

offered to all patients. Such treatment has the goal of approaching normal blood

glucose levels without severe hypoglycemia. This generally means a progression

from two or three daily injections, to multiple injections or the insulin pump

depending on the response to treatment. Critical in determining success are the

patient’s and family’s priorities, abilities, and willingness to adhere.

To achieve near-normal glycemic levels, it is advisable to use algorithms for

adjusting the dose and timing of insulin and meals based on regularly monitored

blood glucose levels or continuous glucose monitoring. They also allow patients

to adjust insulin dose in relation to amount and composition of food and exercise.

Although flexible, such regimens tend to place a great demand on both patient and

physician. The efficacy of insulin algorithms is predicated on

n reasonable and consistent adherence to carbohydrate counting

n adjustment of insulin based on SMBG

n appropriate dosing of insulin before the meal (in young children, the

dose may be given immediately after the meal or split with some pre-

bolus and the rest delivered once the total amount consumed is known)

n a regular pattern of activity and willingness to make adjustments for

unscheduled activities

Algorithms are used to correct for a given glucose value based on the sensitiv-

ity factor or to adjust insulin dosing in anticipation of any blood glucose-altering

factors, e.g., increased carbohydrate intake, most intercurrent stress, or changing

physical activity.

Timing of Prandial Insulin

If using regular insulin, it is preferable to give the insulin injection 30-45 min

before meals so that the peak corresponds to the postmeal glycemic peak, allow-

ing for more optimal glucose disposal. If using a rapid-acting analog, the injec-

tions are given at least 15 minutes before eating. In very young children or

persons with nausea, for whom it is not possible to estimate meal intake before

eating, rapid-acting insulin may be given immediately after the meal or split with

some pre-bolus and the rest delivered once the total amount consumed is known.

76 Medical Management of Type 1 Diabetes

Insulin-to-Carbohydrate Ratios

Patients with type 1 diabetes should be encouraged to learn carbohydrate

counting and to calculate their insulin-to-carbohydrate ratio (I:C) to enhance flex-

ibility in their diet and improve postprandial glucose control. The I:C can vary,

for example, between 1 unit insulin/5 g carbohydrate to 1 unit insulin/25 g car-

bohydrate. For young children, the I:C may be 0.25-0.5 units insulin for every

20-30 g carbohydrate. To determine the I:C ratio, the patient can either 1) eat a

fixed amount of carbohydrates with a meal, adjust the premeal insulin to obtain

adequate postmeal glucose control, and then determine the ratio, or 2) start with an

estimated ratio and adjust it based on the resulting patterns of postprandial glucose

concentrations to obtain adequate postmeal control. The I:C can be determined

by a statistically established formula initially: I:C is estimated at 450 divided by

the total daily dose (TDD) of insulin. For example, the initial estimate of I:C for a

patient taking 25 units of insulin per day would be 18 (1 unit of insulin per 18 grams

of carbohydrate). Subsequently, the I:C can be adjusted by 2-5 g carbohydrates

at a time based on analysis of postprandial glucose records. The I:C is usually the

same at all meals but may be higher (1 unit of insulin to more carbohydrate) in the

morning because of insulin resistance at that time or lower at bedtime. I:C can also

change when there are changes in body weight or the total daily insulin dose.

Correction Bolus Algorithms

All patients on insulin should be provided with correction bolus algorithms to

correct out-of-range glucose values. To do this, the insulin sensitivity, or correc-

tion factor (CF), must be determined for each patient. The insulin CF is defined

as the estimated number of mg/dL (mmol/L) the blood glucose will drop over a

2- to 4-h period following administration of 1 unit rapid-acting insulin. Once this

factor is determined, a corrective bolus or supplemental dose can be estimated

and added to the normal premeal dose or can be given at other times to correct

hyperglycemia.

The CF can be determined by using the “1700 rule,” in which CF = 1700/

TDD. For example, if a patient’s TDD is 50 units insulin, the CF = 1700/50 = 35. In

this case, 1 unit insulin should lower the patient’s blood glucose level by 35 mg/dL

(2 mmol/L). The CF can be used to calculate an individual’s supplemental or cor-

rection bolus dose, where

correction dose = (actual blood glucose [BG] - midtarget BG)/CF.

For most people, midtarget blood glucose is 100 mg/dL (5.5 mmol/L). How-

ever, patients prone to hypoglycemia may have a higher target (120 mg/dL [6.7

mmol/L]), and pregnant patients may have a lower target (80 mg/dL [4.4 mmol/L]).

The correction dose is added to the premeal dose to optimize postmeal glucose

levels. When this is done, it is best to give the dose at least 15-30 minutes before the

meal to start correcting hyperglycemia before eating. A patient’s CF and correction

dose are adjusted upon review of the SMBG records. The correction dose is also

used in sick-day management for correcting hyperglycemia. Because of overlapping

dosing effect when insulin is given again in less than 4 h, the target glucose should

be increased to 140 when dosing at 2 h, i.e.,

correction dose = (BG - 140)/CF.

With CSII, active insulin or insulin on board will help prevent insulin stacking.

Tools of Therapy

Glycemic Targets and Insulin Adjustments

Adjustments of the insulin doses are made on the basis of SMBG measure-

ments and are aimed at achieving target blood glucose values. Target glucose

values are individualized based on the patient’s ability to detect hypoglycemia and

his or her current state of health. In most cases, targets are the normal values of a

person without diabetes. If a child or a person has a proven problem coping with

hypoglycemia, the target may be set higher. If the patient is pregnant, the target

is set toward normal values for a pregnant woman without diabetes.

Adjustments of insulin should be made with care to avoid hypoglycemia and

overinsulinization. Dose adjustments should generally not surpass 1-2 units

(decreases or increases) and should be made only when patterns of out-of-range

glucose levels occur at the same time of day and are not attributed to transient

changes in activity, food intake, or erroneous insulin injection. Ideally, adjust-

ments upward should be made every 2-3 days for short- or rapid-acting insulin

and every 3-5 days for long-acting insulin until the desired blood glucose tar-

gets are achieved. Adjustments downward should be made the next day for unex-

plained hypoglycemia, especially if severe.

There are different ways to achieve treatment targets. One method is to

change the basal insulin to normalize the morning blood glucose level while

avoiding hypoglycemia at 1:00-3:00 a.m. Basal insulin during the day can best

be adjusted when the patient delays or skips a meal and no food intake has

occurred for a minimum of 4 h. Glucose levels should not fluctuate more or

less than 30 mg/dL. Bolus insulin is adjusted based on the postmeal glucose

values if using rapid-acting analogs or the glucose values prior to the next meal

if using regular. Once blood glucose levels are normalized postmeal after a

known amount of carbohydrates for that meal, an I:C can be calculated for

that mealtime. Correction bolus algorithms are also adjusted if the glycemic

response does not bring the glucose into the desired range. If the glycemic

response consistently remains above target range, the insulin CF is lowered. If

the glycemic response is too great and the glucose falls below target range, the

insulin CF is increased.

Treatment options should be individualized according to meal plan, exer-

cise, patient preferences, and lifestyle requirements. SMBG or CGM should

be used frequently to profile glycemic values and to adjust therapy. Optimal

type 1 therapy requires a high degree of knowledge, time, and commitment on

the part of the patient, the family, and the diabetes management team. Insulin

pump therapy requires even more rigorous adherence to SMBG or CGM and

other aspects of management and careful coordination by a team of experienced

professionals.

Barriers to Adherence

Even with initial commitment to intensified insulin therapy from the patient

and diabetes management team, problems can arise. When the goals of the patient

and the diabetes management team are not congruent, attempts at intensive insu-

lin therapy are problematic. Patients may become frustrated by the normal vari-

ability of glucose levels in type 1 diabetes, despite their best efforts. Clinicians

should be alert for signs of “diabetes burnout,” eating disorders, or depression.

78 Medical Management of Type 1 Diabetes

COMMON PROBLEMS IN LONG-TERM THERAPY

Problems with insulin therapy arise regardless of the insulin regimen, and

they must be addressed. Detecting and eliminating patterns of hypoglycemia and

hyperglycemia are the cornerstone of caring for patients with diabetes. This is as

true for the individual with diabetes of several years’ duration as for the newly

diagnosed patient.

Recurrent moderate or severe hypoglycemic reactions signal the need for

evaluation of the insulin regimen, eating and exercise patterns, other diseases or

autoimmune disorders (celiac, Addison’s, thyroiditis) and other lifestyle factors

(e.g., alcohol consumption). Exceptionally low A1C levels may identify patients

at risk for moderate and/or severe hypoglycemia. Some patients have diminished

symptoms of impending hypoglycemia (hypoglycemia unawareness) and, thus,

suffer from recurrent hypoglycemic reactions and/or hypoglycemic seizures.

Hypoglycemia unawareness is more common with longer duration of diabetes.

It also can be exacerbated by antecedent hypoglycemia and conversely partially

reversed by stringent avoidance of hypoglycemia. In patients with hypoglycemia

unawareness, blood glucose targets must be increased, and insulin pump therapy

and use of continuous glucose monitoring should be considered.

Fasting hyperglycemia may occur due to either over- or under-insulinization

overnight. If glucose levels between 2:00 and 4:00 a.m. reveal nocturnal hypo-

glycemia, rebound hyperglycemia (Somogyi effect) may be operative, although

blood glucose levels >200 mg/dL (>11.1 mmol/L) usually do not occur unless

carbohydrates are given to treat hypoglycemia. In this case, a decrease in eve-

ning intermediate- or long-acting insulin or overnight basal rates on the pump is

needed. However, if no nocturnal hypoglycemia can be documented, inadequate

insulin in the early morning hours, due to the dawn phenomenon and/or too little

basal insulin at night may be causative. This should be addressed with either an

increase in presupper or bedtime insulin or a change from a presupper injection

to a bedtime injection schedule. If this fails, insulin pump therapy needs to be

considered with appropriate titration of overnight basal rates.

Disordered eating and inconsistencies in food intake and/or activity, often

associated with psychosocial factors, can be causes of unacceptable day-to-day

glucose control and elevated A1C levels. Additional problems of insulin therapy,

including changes in insulin absorption or sensitivity, surgery, hypoglycemia,

and insulin allergy are discussed in subsequent parts of this chapter or in other

chapters.

INSULIN ALLERGY

Allergic reactions to insulin are increasingly rare with the widespread use of

human insulin. However, patients, particularly those with known atopic diseases,

may exhibit local or systemic allergy to human insulin itself, protamine in NPH,

or the low pH of glargine insulin.

Some allergic-type reactions may be transient or artifactual. Burning, itching,

and hives at injection sites may result from improper injection technique (intra-

dermal rather than subcutaneous injection or injection of cold insulin) or from

localized allergic phenomena.

Tools of Therapy

If symptoms do not resolve and the patient’s injection technique is sound, a

change from one brand or type to another may be in order. True anaphylaxis or

severe asthma, although rare, occurs occasionally and should be treated according

to well-established protocols (e.g., antihistamines, epinephrine). If changing insulin

type does not result in improvement, antihistamines can be prescribed. If atopic

phenomena continue or if systemic symptoms occur, consultation with an allergist

or endocrinologist is recommended for alternative approaches, including insulin

desensitization.

Local Reactions

Lipohypertrophy at the injection site is the most common local complication

of insulin therapy. It is thought to occur as a result of insulin stimulation of fat cell

growth; the exact incidence is unknown. Lipoatrophy is rare with human insulin.

If it does occur, changing brands of insulin may help. If either lipohypertrophy or

lipoatrophy occur, rotation of injection sites with avoidance of the affected sites is

recommended.

Insulin Resistance

Immunological insulin resistance due to antibodies to insulin is exceed-

ingly rare, particularly since the introduction of purified insulins and human

insulin. If it is suspected in a patient with unexplained severe insulin resistance,

i.e., >2 units/kg/day after correction of ketosis with intravenous insulin, insu-

lin antibody titers should be obtained in a reliable research laboratory. If high,

change in insulin brands and type of insulin should be considered. If problems

persist, such patients should be seen by a consultant diabetologist experienced

in the assessment and management of complex problems. Patients with insulin

resistance due to high insulin antibodies sometimes improve with corticosteroid

treatment or other immune suppression therapy. Apparent insulin resistance is

much more likely to occur as the result of the patient’s not taking insulin as

prescribed or using insulin that has precipitated or aggregated from excessive

shaking or heating.

SPECIAL CONSIDERATIONS

Exercise

Because physical activity offers numerous health benefits, it should be

encouraged in every patient with diabetes. In anticipation of the glucose-lowering

effects of exercise, e.g., 30-45 min of moderate to vigorous physical activity, it

may be necessary to increase carbohydrate intake or decrease the insulin dose

to avoid hypoglycemia during or after exercise. Exercise-related hypoglycemia

results from increased glucose uptake and utilization by the exercising muscle.

In the case of prolonged exercise (lasting >1-2 h), it is necessary to reduce the

insulin dose because hypoglycemia can occur many hours after exercise. General

guidelines for avoiding exercise-related hypoglycemia are given in Table 3.4.

80 Medical Management of Type 1 Diabetes

n A decrease in prebreakfast rapid- or short-acting insulin is recommended if

exercise is done within 3 h of breakfast.

n Decrease prelunch rapid- or short-acting insulin and/or morning NPH

or exercise occurring in the late morning or early afternoon.

n Decrease presupper rapid- or short-acting insulin in anticipation of exer-

cise occurring after supper.

n Suspend or decrease basal insulin delivery with the pump during and

after strenuous exercise.

Management During Acute Illnesses

The increased secretion of counterregulatory hormones and decreased activ-

ity even in the face of reduced caloric intake or vomiting may increase insulin

requirements. Blood glucose and urine or blood ketone levels should be tested

frequently (e.g., every 1-4 h or each time the patient urinates). The physician

should be contacted immediately for advice if prior written guidelines are not

known by the patient or family member. The following guidelines, based on

whether the patient is able to take food or liquids by mouth, are useful for man-

aging a patient during an illness.

An illness not accompanied by nausea or vomiting (e.g., minor infection

or trauma requiring bed rest). If activity is normal, give the usual dose of basal

insulin plus a correction bolus every 2-4 h as needed according to the blood glu-

cose and ketone tests. If able to drink or eat, give, in addition to the correction

bolus, the meal bolus insulin to cover the carbohydrate consumed. If an I:C is not

known, give ~1-1.5 units insulin for every 15 g carbohydrate consumed.

Table 3.4 General Guidelines for Avoiding Exercise-Induced

Hypoglycemia in Insulin-Treated Patients

n Measure blood glucose before, during, and after exercise.

n Unplanned exercise should be preceded by extra carbohydrate, e.g., 15-30 g per

30 min exercise; insulin may need to be decreased after exercise.

n If exercise is planned, insulin dosages can be decreased before and after exercise

according to the exercise intensity and duration as well as the personal experience of the

individual with diabetes.

n Patients on pumps may suspend or decrease their basal rate during and after exercise.

n During exercise, easily absorbable carbohydrate may need to be consumed.

n After exercise, extra carbohydrate may be necessary and may be added to meals and

snacks.

n Athletes and those who exercise for fitness need specific instructions and training on

self-management skills for exercise.

n Exercise can cause hypoglycemia during the night and bedtime snacks or reduction in

basal insulin needs to be considered.

Adapted from Berger M: Adjustment of insulin and oral agent therapy. In Handbook of Exercise and

Diabetes. Ruderman N, Devlin JT, Schneider SH, Kriska A, Eds. Alexandria, VA, American Ðiabetes

Association, 2002, p. 374.

Tools of Therapy

If activity is reduced and the patient is confined to bed, caloric intake should

be reduced by approximately one-third. The reduction in caloric intake com-

pensates for the inactivity. The insulin adjustment is the same as for an illness

without bed rest.

An illness accompanied by nausea, vomiting, or marked anorexia. Blood

glucose and urine or blood ketones should be measured as soon as possible and

every 2-4 h until the illness or situation has resolved. If there are initial aber-

rations of glycemia, repeat glucose measurements may need to be done hourly,

The insulin dose must never be omitted, because this could lead to ketoacidosis.

If glucose is >240 mg/dL (>13.3 mmol/L) and ketones are large, the patient

should give a correction bolus by syringe, call the health care team, and con-

sider emergency department care for probable diabetic ketoacidosis. If glucose

is >240 mg/dL (>13.3 mmol/L) and ketones are not large, the patient can take a

correction bolus every 2-4 h and drink noncaloric fluids until the situation has

resolved. If on CSII, the infusion set and tubing must be changed and the cor-

rection bolus given by injection. If the glucose is <240 mg/dL (<13.3 mmol/L)

and ketones are large, the patient can take a correction bolus or an insulin injec-

tion every 2-4 h and consume caloric fluids as tolerated until the situation is

resolved. When in doubt or the situation is not resolving, the patient should

contact the health care provider.

Vomiting that occurs after administration of the usual morning dose of

insulin. Sips of sugar-containing fluids should be given every 20-30 min to main-

tain blood glucose levels between 100 and 180 mg/dL (5.67 and 10.0 mmol/L).

If vomiting persists and blood glucose level falls to <100 mg/dL (<5.6 mmol/L),

consider giving “low-dose” glucagon at 1 unit of mixed glucagon on the insulin

syringe for every year, up to 15-20 units. This might be sufficient to resolve

hypoglycemia and associated nausea/vomiting and allow for the ingestion of

small amounts of sugar-containing fluids as above. If hypoglycemia persists, the

patient may require intravenous glucose therapy. A subcutaneous injection of

remaining dosage of glucagon, or if not previously given “low-dose” glucagon, a

full dose of glucagon depending on age should be given at home before departing

if the patient lives some distance from the hospital.

Whenever the patient is sick and has blood glucose levels >240 mg/dL (>13.3

mmol/L) and moderate or large ketonuria, the diabetes team should be advised

immediately or the patient should be brought to the emergency room, because this

could reflect impending ketoacidosis. Repeated vomiting lasting more than 4-6 h

or accompanied by high fever, abdominal pain, severe headache, or drowsiness may

require that the patient be evaluated by a health care provider to ascertain whether he

or she has a serious infection, appendicitis, meningitis, or other condition requir-

ing antibiotics, surgery, or intensive medical care in a hospital setting.

Treatment of Diabetes in Newborns and Infants

Transient or permanent neonatal diabetes (NDM) occurs before 6 months

of age, including in newborn infants. Neonatal diabetes is a rare monogenic

form of diabetes occurring in 1 in 100,000-500,000 live births. Affected infants

82 Medical Management of Type 1 Diabetes

are insulin deficient leading to hyperglycemia, dehydration, and ketoacidosis;

neonatal diabetes can be mistaken for the much more common type 1 diabetes,

but type 1 diabetes usually does not occur before 6 months of age. In about half

of the cases of neonatal diabetes, the condition is lifelong and is called perma-

nent neonatal diabetes, and in half, it is transient and disappears during infancy,

although it can reappear later in life. Specific genes that can cause NDM have

been identified.

Due to insulin deficiency, these babies usually suffer from severe intrauterine

malnutrition and, therefore, are small for their gestational age. As a result of

hypoinsulinema, and intrauterine growth failure, these infants must be treated

with exogenous insulin and may require high doses of 1-2 units/kg/day. Insulin

requirements are best established by starting a continuous intravenous insulin

infusion at rates that provide at least 0.5 units/kg/day. Insulin treatment is sim-

plified by using diluted insulins (e.g., a solution containing 10 units/ml) so that

inadvertent overdoses do not occur. It is very important to dilute the insulin with

diluents received directly from the manufacturer. After birth, some infants fail

to gain weight and grow as rapidly as expected; however, appropriate diabetes

management improves and may normalize growth and development.

Type 1 diabetes can start in infancy, usually after 6 months of age. To dif-

ferentiate type 1 from a monogenic form of neonatal diabetes, antibodies should

be obtained as well as specific gene analyses. The treatment of type 1 diabe-

tes in infancy is similar to that described for the infant with neonatal diabetes.

Insulin requirements vary, and care of these patients should be supervised by an

experienced specialist. The type of regimen used must be individualized depend-

ing on the ability to control hyperglycemia without an excess of hypoglycemia,

since both may be particularly detrimental to the developing brain. Many infants

are placed on CSII with dilute insulin, since this treatment might best facilitate

decreasing extremes of glycemic variability.

CONCLUSION

Type 1 diabetes is characterized by a progressive decline of insulin secretion

until its disappearance 1-5 years after diagnosis. Thus, people with type 1 diabe-

tes are dependent on insulin to survive. Insulin therapy should always be coupled

with SMBG, monitoring of carbohydrate intake, and proper precautions for ill-

ness and physical activity. CGM should be considered as a method to improve

glucose control. In this way, insulin therapy can be adjusted safely and effectively

and individualized to age, lifestyle, eating habits, state of health, and physical

activity. Effective insulin therapy helps the patient avoid extreme metabolic cri-

ses, such as hypoglycemia and ketoacidosis, achieve and maintain good glycemic

control, and reduce the risk of diabetes complications.

BIBLIOGRAPHY

Ahern JAH, Boland EA, Doane R, Ahern JJ, Rose P, Vincent M, Tamborlane

WV: Insulin pump therapy in pediatrics: a therapeutic alternative to safely

lower HbA1c levels across all age groups. Pediatr Diabetes 3:10-15, 2002

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Agrawal P, Welsh JB, Kannard B, Askari S, Yan Q, Kaufman FR: Usage and

effectiveness of the low glucose suspend feature of the Medtronic Paradigm

Veo insulin pump. J Diabetes Sci Technol 5:1137-1141, 2011

American Diabetes Association: Intensive Diabetes Management. 5th ed. Wolfs-

dorf J, Ed. Alexandria, VA, American Diabetes Association, 2012

American Diabetes Association: Practical Insulin: A Handbook for Prescribers. 3rd

ed. Alexandria, VA, American Diabetes Association, 2011

Armstrong DU, King AB: Basal insulin: continuous glucose monitoring reveals

less overnight hypoglycemia with continuous subcutaneous insulin infusion

than with glargine (Abstract). Diabetes 51 (Suppl. 2):A92, 2002

Bode BW, Tamborlane WV, Davidson PC: Insulin pump therapy in the

21st century. Postgrad Med 111:69-77, 2002

Bolderman K: Putting Your Patients on the Pump. Alexandria, VA, American

Ðiabetes Association, 2002

Bruttomesso D, Pianta A, Crazzola D, Scaldaferri E, Lora L, Guarneri G, Mon-

gillo A, Gennaro R, Miola M, Moretti M, Confortin L, Beltramello GP,

Pais M, Baritusso A, Casiglia E, Tienga A: Continuous subcutaneous insulin

infusion (CSII) in the Veneto region: efficacy, acceptability, and quality of

life. Diabet Med 19:628-634, 2002

Cersosimo E, Jornsay D, Arce C, Rieff M, Feldman E, DeFronzo R: Improved

clinical outcomes with intensive insulin pump therapy in type 1 diabetes

(Abstract). Diabetes 51 (Suppl. 2):A128, 2002

Davidson PC, Hebblewhite HR, Bode BW, Richardson PL, Steed RD, Welch

NS, Johnson J: Statistical estimates for CSII parameters: carbohydrate-to-

insulin ratio (CIR); correction factor (CF); and basal insulin. Diabetes Technol

Ther 5:A28, 2003

DeVries JH, Snoek FJ, Kostense PJ, Masurel N, Heine RJ: A randomized trial

of continuous subcutaneous insulin infusion and intensive injection therapy

in type 1 diabetes for patients with long-standing poor glycemic control.

Diabetes Care 25:2074-2080, 2002

Dunn FL, Nathan DM, Scavini M, Selam JL, Wingrove TG: The Implantable

Insulin Pump Trial Study Group: Long-term therapy of IDDM with an

implantable insulin pump. Diabetes Care 20:59-63, 1997

Hanaire-Broutin H, Broussolie C, Jeandidier N, Renard E, Guerci B, Haardt

M-J, Lassmann-Vague V: The EVADIAC Study Group (Evaluation dans

le Diabète du Traitement par Implants Actifs): Feasibility of intraperitoneal

insulin therapy with programmable implantable pumps in IDDM: a multi-

center study. Diabetes Care 18:388-392, 1995

Hattersley A, Bruining J, Shield J, Njølstad P, Donaghue K: International

Society for Pediatric and Adolescent Diabetes (ISPAD) Clinical Practice

Consensus Guidelines 2006-2007: The diagnosis and management of

monogenic diabetes in children. Pediatric Diabetes 7:352-360, 2006

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Henry RR, Mudaliar SRD, Howland WC III, Chu N, Kim D, An B, Reinhardt

RR: Inhaled insulin using the AERx insulin Diabetes Management System

in healthy and asthmatic subjects. Diabetes Care 26:764-769, 2003

Lepore G, Dodesini AR, Nosari I, Trevisan R: Both continuous subcutaneous

insulin infusion and a multiple daily insulin injection regimen with glargine

as basal insulin are equally better than traditional multiple daily insulin

injection treatment. Diabetes Care 26:1321-1322, 2003

Linkeschova R, Raoul M, Bott U, Berger M, Spraul M: Less severe hypoglycae-

mia, better metabolic control, and improved quality of life in type 1 diabetes

mellitus with continuous subcutaneous insulin infusion (CSII) therapy: an

observational study of 100 consecutive patients followed for a mean of

2 years. Diabetic Med 19:746-751, 2002

Litton J, Rice A, Friedman N, Oden J, Lee MM, Freemark M: Insulin pump

ŧherapy in toddlers and preschool children with type 1 diabetes mellitus.

J Pediatr 141:490-495, 2002

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National Institutes of Health, National Institute of Diabetes and Digestive

and Kidney Diseases. The genetic landscape of diabetes. Available at: http://

www.ncbi.nlm.nih.gov/books/NBK1667. Accessed 29 March 2012

Phillip M, Battelino T, Rodriques H, Danne T, Kaufman F: Use of insulin

pump therapy in the pediatric age group. Consensus statement from the

European Society for Pediatric Endocrinology, the Lawson Wilkins Pedi-

atric Endocrine Society, and the International Society for Pediatric and

Adolescent Diabetes. Endorsed by the American Diabetes Association and

the European Association for the Study of Diabetes. Diabetes Care 30:1653-

1662, 2007

Pickup J, Matack M, Kerry S: Glycaemic control with continuous subcutane-

ous insulin infusion compared with intensive insulin injections in patients

with type 1 diabetes: meta-analysis of randomized control trials. BMJ 324

(7339):705, 2002.

Rudolph JW, Hirsch IB: Assessment of therapy with continuous subcutaneous

insulin infusion in an academic diabetes clinic. Endocrine Pract 8:401-405, 2002

Santiago JV, White N: Diabetes in childhood and adolescence. In International

Textbook of Diabetes Mellitus. 2nd ed. Alberti KGMM, Zimmet P, DeFronzo

RA, Eds. Chichester, U.K., Wiley, 1997, p. 1095-1122

Skyler JS: Insulin therapy in type 1 diabetes mellitus. In Current Therapy of

Ðiabetes Mellitus. DeFronzo RA, Ed. St. Louis, MO, Mosby, 1998, p. 36-49

Skyler JS, Cefalu WT, Kourides IA, Landschulz WH, Balagtas CC, Cheng SL,

Gelfard RA: Efficacy of inhaled human insulin in type 1 diabetes mellitus: a

randomized proof-of-concept study. Lancet 357:331-335, 2001

Wolpert H (Ed.): Smart Pumping for People with Diabetes: A Practical Approach to Master-

ing the Insulin Pump. Alexandria, VA, American Diabetes Association, 2002

Tools of Therapy

TREATMENT WITH AMYLIN ANALOG PRAMLINTIDE

ype 1 diabetes manifests with absolute insulin deficiency, and for the past

80 years, insulin replacement therapy has been the only pharmacologi-

cal treatment available for this disease. Despite considerable advances in

insulin therapy, such as the development of insulin pumps and, more recently,

rapid- and long-acting insulin analogs, many patients with type 1 diabetes are

still unable to achieve and maintain optimal glycemic control.

Among the clinical barriers that hinder the attainment of glycemic goals

with insulin therapy alone are the increased risk of hypoglycemia, postprandial

hyperglycemia, excessive glucose fluctuations throughout the day, and undesired

weight gain. More recently, it has been recognized that pancreatic b-cells secrete

another glucoregulatory hormone, amylin, which is normally cosecreted with

insulin in response to meals. Consequently, the autoimmune-mediated destruc-

tion of pancreatic b-cells in type 1 diabetes results in an absolute deficiency not

only of insulin, but also of amylin.

Amylin is a 37-amino acid neuroendocrine hormone that binds with high

affinity to certain areas of the brain and complements the effects of insulin in

postprandial glucose control. Specifically, while insulin is the major hormone in

the regulation of glucose disposal (efflux) out of the circulation, amylin regulates

the inflow of glucose into the circulation after meals. This is achieved by sup-

pression of glucagon secretion and regulation of gastric emptying. In addition,

amylin has been shown to reduce food intake and body weight in laboratory

animals, suggesting that it may also act as a physiological satiety signal.

The findings that amylin is normally cosecreted with insulin, that it comple-

ments the effect of insulin, and that it is completely deficient in type 1 diabetes

led to the hypothesis that amylin replacement may convey additional benefits to

patients with type 1 diabetes when added to existing insulin regimens. Human

amylin itself is not optimal for clinical use because of its insolubility and ten-

dency to self-aggregate; thus, a soluble nonaggregating equipotent amylin ana-

log, pramlintide, was developed.

Pramlintide is an adjunct to insulin therapy in people with type 1 or type 2

diabetes. Like insulin, pramlintide is given via subcutaneous injection. In short-

term studies (days or weeks) of patients with type 1 diabetes, addition of pram-

lintide to insulin injections before meals reduced postprandial glucose excursions

by at least 75%, regardless of whether pramlintide was used with regular insulin

or a rapid-acting insulin analog. Adjunctive treatment with pramlintide reduced

excessive glucose fluctuations over the course of the day, as demonstrated in

a 4-week study with a continuous glucose-monitoring device in an intensively

treated type 1 diabetes patient. Note that these effects were achieved with pram-

lintide doses (30 and 60 µg) that yield a plasma pramlintide profile similar to

the normal postprandial amylin response in healthy subjects, indicating that

the improvement in postprandial glucose control is achieved via physiological

replacement of the absent amylin action. Additional studies in patients with type

1 diabetes have shown that the improvement in postprandial glucose control

with pramlintide is attributable to both a correction of postprandial glucagon

hypersecretion, thereby controlling excessive glucose output from the liver, and

a slowing of gastric emptying, thereby controlling glucose inflow from the gut.

86 Medical Management of Type 1 Diabetes

These pramlintide effects are entirely consistent with the known physiological

functions of amylin.

In studies of 6-12 months duration in patients with type 1 diabetes, addition

of pramlintide to preexisting insulin regimens led to a significant A1C reduc-

tion of ~0.3-0.5% compared to placebo and a doubling of the proportion of

patients achieving recommended glycemic targets (A1C <7%). In a longer term

study (29 weeks), the safety, efficacy, and dose escalation of pramlintide showed

with mealtime insulin reduction, followed by insulin optimization. Pramilintide

was shown to drecrease postprandial glucose excursions and weight, and with a

decreased prandial insulin dose and without severe hypoglycemia.

This makes pramlintide the first pharmacological agent and hormone

replacement other than insulin shown to improve long-term glycemic con-

trol in patients with type 1 diabetes. It is important to note that the glycemic

improvement with pramlintide was not accompanied by the long-term increases

in body weight and severe hypoglycemia typically seen when glycemic control

is improved by increasing the dose of insulin. On the contrary, compared to

placebo, pramlintide treatment was associated with a relative decrease in insulin

use and reduction in body weight that was most pronounced (~1.5-3 kg) in over-

weight and obese patients (lean patients did not have unwarranted weight loss).

Pramlintide treatment was generally well tolerated; the most common adverse

event was mild nausea, which typically occurred during the first few weeks of

therapy and dissipated over time.

In summary, amylin replacement with pramlintide elicits a combination of

clinical benefits that addresses some of the unresolved challenges with insulin

therapy in type 1 diabetes. Adjunctive therapy with pramlintide is useful for

those patients with type 1 diabetes in whom there are excessive unpredictable

glucose fluctuations, postprandial hyperglycemia, undesired weight gain, or

repeated episodes of insulin-induced hypoglycemia that hinder the achievement

of glycemic targets. The clinical benefits of pramlintide are achieved by replac-

ing the action of a second, naturally occurring b-cell hormone that is deficient

in type 1 diabetes. By better matching the rate of glucose inflow to the rate of

insulin-mediated glucose disposal, pramlintide improves glucose control via a

unique mechanism of action that is distinct from, and complementary to, the

action of insulin and its analogs.

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Baron AD, Kim D, Weyer C: Novel peptides under development for the

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Buse JB, Weyer C, Maggs DG: Amylin replacement with pramlintide in type

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Edelman SV, Weyer C: Unresolved challenges with insulin therapy in type 1

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Tools of Therapy

Edelman S, Garg S, Frias J, Maggs D, Wang Y, Zhang B, Strobel S, Lutz K,

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Kornstein J, Schwartz S, Guiterrez M, Kolterman OG: Mealtime amylin

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88 Medical Management of Type 1 Diabetes

MONITORING

onitoring, performed by patients, families, and their diabetes manage-

ment teams, is an integral feature of diabetes care. Specifically, results

of blood or interstitial glucose monitoring are useful in preventing

hyperglycemia and hypoglycemia, reducing glycemic excursions, and adjusting

insulin and other medications such as pramlintide, diet, and exercise so that

target blood glucose levels are achieved. Additionally, testing for urine or blood

ketones provides an early warning sign of impending ketoacidosis.

PATIENT-PERFORMED MONITORING

Patients can manage their diabetes effectively and safely only if they are able

to perform SMBG. In certain circumstances (infants, young children, hospital-

ized or incapacitated patients), monitoring may be performed by family mem-

bers, school personnel, child care providers, and health care providers.

SMBG is a direct method of testing glucose that allows patients to determine

their glucose levels anywhere (at home, school, or work) and to adjust therapy on

the basis of accurate and timely results. To perform SMBG, a drop of blood is

obtained from a fingertip or alternative site by use of a sharp lancet, usually with

the aid of an automatic spring-loaded puncturing device. The blood is then applied

to a chemically impregnated or electrochemical strip, and after a specified time, the

result is quantitated and displayed on the meter. In most meters, the results, as well

as additional data (date, time, and, in some cases, additional data entered by the

patient, such as whether the reading is pre or postprandial), are stored in memory

for later analysis.

Alternative site testing is available with some meters that need only a small

amount of blood (<1 mL). Such testing, usually performed on the forearm but

also possible at other sites (heel of hand, thigh), is reliable and correlates well

with fingerstick testing in the premeal or fasting state but can have up to a 15- to

30-min lag if testing is done when glucose levels are changing rapidly (postmeal

or with hypoglycemia). Therefore, it is recommended that patients be aware of

this lag and not make decisions based on alternative testing at these times, but

rather test the fingertip.

Many commercially available strips and meters have been evaluated and are

relatively reliable and reasonably accurate. Lists of SMBG products are found in

the Resource Guide, published annually in the January issue of Diabetes Forecast, the

American Diabetes Association’s magazine. With appropriate education, most

patients can perform the technique successfully. However, office return demon-

strations of the patient’s skills and the use of quality control techniques at home

are essential. Patients should be encouraged to bring their meters to every office

visit to assess their accuracy and, if possible, to download the memory. Down-

loads have log book displays calling out values above and below target, mean val-

ues, pie charts, graphs, etc. Inaccurate measurements can be obtained with faulty

meters, wrong coding of strips, unclean or wet hands, or use of control solutions

instead of blood for testing. Using inaccurate measurements to make treatment

adjustments can be more dangerous than having no measurements at all.

Tools of Therapy

Frequency of SMBG

The frequency and timing of glucose monitoring should be dictated by the

particular needs and goals of the patient. If the goal is to obtain near-normal glu-

cose levels and prevent hyperglycemia and hypoglycemia and extremes of glycemic

excursions, then most patients with type 1 diabetes should do a minimum of 4-6

tests per day (before meals to calculate prandial insulin doses and before bedtime

to protect against hypoglycemia at night.) Additional testing after meals may be

needed periodically or regularly to adjust prandial insulin doses. Testing before,

during, and/or after exercise can help the patient avoid serious hypoglycemia (see

Exercise, page 122). Adding a test periodically in the middle of the night is par-

ticularly important for patients who aim for near-normal blood glucose levels,

those with unexplained fasting hyperglycemia, and for any patient during illness

or after intense physical activity. Patients should vary testing times to learn about

their blood glucose patterns over the entire day. Patients who are ill (Table 2.7),

pregnant, or whose usual schedule has changed require more frequent monitoring.

Adjusting Insulin Dose

SMBG results are crucial in making appropriate insulin adjustments to opti-

mize glycemic control and prevent hypoglycemia and avoid hyperglycemic crisis.

Insulin dose adjustments are covered earlier in this chapter under the section

Glycemic Targets and Insulin Adjustments. SMBG results are also used at meal-

times to calculate a correction bolus in addition to the meal bolus needed to cover

that meal. Thus, most patients should be encouraged to monitor a minimum of

4-6 times a day (before and after meals and at bedtime and during the night), with

additional monitoring at other times (during hypoglycemia, exercise, illness) to

ensure safe and effective therapy. Since there is evidence that more monitoring

improves glucose levels, it is not uncommon to see patients monitoring 8-10 or

more times per 24 hours, either routinely or occasionally.

Pregnant women need to perform SMBG more frequently (8-10, or more,

times daily) to adjust insulin doses to obtain stringent glycemic targets and to

avoid hypoglycemia. As with other elements of diabetes management, the pre-

scription for glucose monitoring must be individualized.

The value of SMBG is not limited to adjustments in insulin dose. Patients

with suspected nocturnal hypoglycemia can check their blood glucose levels at

3:00 a.m. SMBG is a valuable educational tool to help the patient differentiate

between symptoms truly arising from hypoglycemia or hyperglycemia and those

from other causes.

Common Causes of Errors

Despite the relative simplicity of SMBG, the information is not free of errors.

Many of the previous problems with SMBG have been resolved with test strips

that do not require wiping, meters with built-in timers, meters with memory, and

strips that do not require coding. The most common problems now with SMBG,

independent of specific methodologies, include the use of an inadequate drop

90 Medical Management of Type 1 Diabetes

of blood on the strip, wet or dirty hands, use of the control solution instead of

blood, or a poorly calibrated meter. These problems stress the need to provide

proper patient education and training in SMBG. Finally, some patients report

their results inaccurately, perhaps to please their spouses, parents, or diabetes

management team with the right results. The use of meters that automatically

store glucose results in an electronic memory may simplify the recording, report-

ing, and analysis of SMBG; these results should be downloaded before or during

office visits. Faxing data or transmitting through emails, with proper precautions

to protect patient privacy, saves considerable amounts of time and enhances com-

pliance to SMBG and intensive diabetes management.

Successful SMBG

If the goal of SMBG is to improve glycemic control, the diabetes manage-

ment team should ensure that the patient

n reviews results of glycemic patterns with the diabetes management team

n responds to the results by making appropriate changes in the insulin

regimen

n receives the necessary psychosocial support and technical guidance

n monitors as frequently as recommended

n reads and reports tests accurately

n uses additional SMBG during intercurrent illnesses, exercise, traveling,

and when routine not followed

To support successful glycemic control, there should be mutual efforts to

maintain education, motivation, and adherence. Furthermore, it is essential for

the diabetes management team to provide feedback by monitoring progress with

A1C (eAG) tests every 3 months.

GLUCOSE SENSORS

Continuous interstitial glucose sensing is an adjunct to SMBG that provides

additional data to optimize glycemic control and alarms to help prevent hypogly-

cemic and hyperglycemic crises. Several different systems have been approved in

the US by the FDA, and others are in development. The devices that are available

are calibrated by fingerstick SMBG measurements and then sense glucose in the

interstitial fluid using glucose oxidase enzymatic methodology. Interstitial fluid

has been shown to correlate well with blood glucose, and the glucose concentra-

tion in the interstitial fluid has been shown to reflect glucose concentrations and

glucose dynamics in the brain. However, there is a physiological lag between the

interstitial fluid and the blood. This lag is usually <5 min in the fasting or premeal

state but can be up to 13 min in the postprandial state. As a result of the lag time

and other factors, these devices are currently recommended for use as an adjunct

to, not a replacement for, SMBG. The glucose trends and alarms/alerts, rather

than the absolute glucose values, obtained from these devices are used to make

therapy changes to optimize glucose control. For immediate therapy decisions,

such as deciding on premeal insulin doses or treatment of hypoglycemia, patients

should use the SMBG results. Most continuous glucose sensors can be worn for

3-7 days.

Tools of Therapy

The original continuous glucose monitoring system (CGM) was used like a

Holter-style monitor system and measured glucose continuously in interstitial

fluid for up to 72 h. The data was not displayed to the patient in real-time, but

was used by a physician or member of the diabetes team for retrospective moni-

toring and interpretation of the readings. To use this system, an electrochemical

sensor was inserted by an insertion device into the subcutaneous tissue (usually

the abdomen, buttocks, or back) and worn for up to 72 h. The sensor used in the

original systems measured glucose every 10 s and provided an average glucose

every 5 min for up to 288 readings per day. These readings were collected and

stored in a monitor connected by a cable to the sensor. Calibration by fingerstick

blood glucose measurements was done at least three times per day with entry of

the value into the monitor. Patients were also instructed to keep a food diary and

enter event markers for specific behaviors such as eating, insulin administration,

exercise, and hypoglycemia symptoms. After wearing the device, the sensor was

removed and the monitor was downloaded into a computer for further analysis

and evaluation by the health care provider and the patient.

Retrospective (also called professional or blinded) CGM devices used now

employ the same sensor that is used with real-time CGM, and instead of trans-

mitting the interstitial glucose values to a monitor, the information is stored

and downloaded to a computer program at the end of the sensor wear (3-7 days

depending on sensor life). During the use of retrospective CGM, the patient

must calibrate the sensor with SMBG and use SMBG to manage their diabetes.

Patients are also instructed to keep a food diary and enter event markers for spe-

cific behaviors such as eating, insulin administration, exercise, and hypoglycemia

symptoms. These systems are used one time or at repeated intervals to obtain

continuous glucose monitoring information when the patient is not ready to wear

a real-time device. The 288 glucose values per day can be used to determine

the presence of hypoglycemia, particularly at night, the dawn phenomenon, and

postprandial hyperglycemia. It is of particular value in those suspected of having

hypoglycemia unawareness and can be used at the time of a change in the dia-

betes regimen, such as when switching from MDI to CSII. Retrospective CGM

can also be used to help patients understand the effect of certain lifestyle choices,

such as glycemic patterns associated with exercise or after the ingestion of specific

foods. The uploaded data is displayed on a number of pages including a log book

that calls out values above and below glycemic targets, individual tracings by day,

mean glucose by day and time of day, pie charts, and area and percent above and

below targets. Retrospective CGM is also used in research protocols to compare

the glycemic outcomes between the groups being evaluated in the research study.

Real-time Continuous Glucose Monitoring System (CGM)

Continuous glucose monitoring systems are meant to be worn chronically or

intermittently by the same patient and provide real-time as well as stored glucose

data (which can be uploaded through a computer program for retrospective anal-

ysis). The system consists of a sensor, a monitor, and a transmitting device (which

sends in real-time the signal from the sensor to the monitor). When CGM is inte-

grated with an insulin pump, referred to as sensor-augmented pump therapy, the

pump itself is used as the monitor and the stored glucose and pump data can be

uploaded together. Real-time CGM systems have alarms for present high and low

92 Medical Management of Type 1 Diabetes

glucose levels, alarms for a rapid change in glucose value, and predictive alarms to

warn of impending hypoglycemia and hyperglycemia.

The first linkage between sensor glucose and insulin delivery (an automated

step in the path to the “closed loop” pump or artificial pancreas) is low glucose

suspend. Low glucose suspend allows for suspension of insulin delivery when a

low glucose threshold, determined by the patient and health care team, has been

reached. Insulin is suspended for a maximum of 2 h; however, the patient may

interrupt the suspension and resume insulin delivery at any time. Early data on

the use of this system suggests that it decreases the time spent in hypoglycemia

without increasing hyperglycemia. The predictive low glucose suspend feature

uses a prediction algorithm to prevent, not just mitigate, hypoglycemia. In addi-

tion, investigators across the globe are working on closed-loop algorithms for

nighttime, as well as fully closed-loop systems that would automate insulin deliv-

ery day and night.

Although originally there were only short-term and not rigorously controlled

studies on CGM, there have been an increasing number of longer-term studies

(6-12 month study phase with up to 12-18 month continuation phase) in adults

and children showing that CGM is associated with reduced glycemic variability

(less time spent in the hyperglycemic and hypoglycemic ranges) and improved

glycemic control. In subjects with A1C < 7%, CGM usage has been shown to

assist in maintaining target A1C levels while limiting the risk of hypoglycemia.

These studies have also shown that the greater the sensor usage, the more the

reduction in A1C levels. A recent meta-analysis of 6 randomized controlled trials

involving 449 patients showed that CGM was associated with significant reduc-

tion in A1C. Those with the highest A1C and those who used sensors the most

had the greatest reduction in A1C. The devices and sensors are expensive and

may not be covered by third-party payors. However, the devices are increasingly

being prescribed, especially for children and adults with severe hypoglycemia. In

2008, the ADA recommendation (level E, based on expert opinion) was that such

systems may be a useful supplemental tool to SMBG for selected patients with

type 1 diabetes, who have demonstrated they can use these devices.

Advances continue to be made with next generation glucose oxidase sensors

being more accurate, smaller, more comfortable, and of longer duration. Research

continues not only with this methodology, but with other methods to measure

glucose in the interstitial fluid as well as in other parts of the body. The ultimate

goal is to develop CGM methodologies that will replace SMBG and be reliable

enough for the artificial pancreas.

KETONE TESTING

The ketone bodies acetoacetate (AcAc), acetone, and b-hydroxybutyric acid

(b-HBA) are catabolic products of free fatty acids. Determinations of ketones

in the urine and blood are widely used as adjuncts for both the diagnosis and

ongoing monitoring of DKA. Measurements of ketone bodies can be routinely

performed both in the office/hospital setting and by patients at home.

Urine ketone testing remains the most commonly used method to detect

impending ketosis at home. Most urine methods use reagent strips containing

nitroprusside that form a colorimetric reaction on contact with AcAc (and in

Tools of Therapy

some strips acetone), resulting in a purple color. Care should be taken not to use

out-of-date strips. The strips are manually read as measuring negative, small,

moderate, or large ketones. Urine methodologies do not measure b-HBA and are

thus not useful in monitoring the response to DKA treatment, because AcAc and

acetone may increase as b-HBA falls during successful treatment of DKA.

Testing for ketonuria should be a regular feature of sick-day instructions

and should be done every time blood glucose levels are consistently >240 mg/dL

(>13.3 mmol/L). The presence of persistent moderate or large amounts of

ketones in the urine suggests the possibility of impending or established DKA

and should prompt patients to adjust insulin as recommended or seek assistance

by calling their health care provider. Note that positive urine ketone readings are

found in up to 30% of first morning urine specimens from pregnant woman (with

and without diabetes), during starvation, and after hypoglycemia.

Blood ketone testing is also available for home and office/hospital use. Most

blood methods measure b-HBA, which is the predominant ketone in DKA. Ref-

erence intervals for b-HBA differ among the assay methods, but concentrations

<0.5 mmol/L are considered normal, 0.6-1.5 mmol/L indicate the potential

for DKA, and >1.5 mmol/L indicate high risk for DKA or that DKA is already

present.

Specific measurements of b-HBA in blood can be used by both the patient

and health care provider for the diagnosis and monitoring of DKA. Testing for

blood ketones is not mandatory for either the patient or the health care provider

because the patient can use urine testing to troubleshoot hyperglycemia and the

health care provider can use measurements of serum CO₂, anion gap, and pH to

diagnose and monitor DKA treatment. However, blood ketone testing is much

more specific than urine testing and much quicker and easier than these hospital

laboratory methods, and thus has a role in the prevention, diagnosis, and manage-

ment of DKA.

PHYSICIAN-PERFORMED GLUCOSE MONITORING

Because blood glucose levels can fluctuate widely in type 1 diabetes, sporadic

testing in the physician’s office is not sufficient as the sole means of monitoring.

Intermittent testing does not reliably predict glucose levels at other times or the

level of chronic glycemic control. Laboratory glucose determinations by a cali-

brated meter or approved instrument can be performed, if needed, to validate the

accuracy of patient-performed monitoring and meter accuracy.

Glycated Hemoglobin (A1C Test)

The introduction of the A1C assay has revolutionized the ability to follow

glucose control over time. When hemoglobin and other proteins are exposed to

glucose, the glucose becomes attached to the protein in a slow, nonenzymatic, and

concentration-dependent fashion. The concentration of glycated hemoglobin best

reflects the mean blood glucose concentration over the preceding 6-10 weeks.

This measurement is performed on a single tube of blood or with a fingerstick

capillary sample, and when correctly performed by a reliable laboratory or certified

94 Medical Management of Type 1 Diabetes

kit, the test is unaffected by acute changes in blood glucose; therefore, the test can

be performed at any time during the day.

The Diabetes Control and Complications Trial (DCCT) established the

major role of glycemic control in the development and progression of microvas-

cular complications in type 1 diabetes. Although glycemic control can be assessed

directly by analyzing multiple blood glucose levels over time, the A1C is strongly

associated with the mean of the blood glucose values and easier to obtain. How-

ever, factors other than just mean blood glucose have been shown to affect A1C;

these include biological variation for glycation and glucose variability or insta-

bility. The contribution of glycemic variability or instability to A1C in studies

derived from DCCT data appears to be minor. This suggests that glucose vari-

ability, particularly the instability of postprandial values, may influence outcome

through other pathways, such as oxidative stress.

Assay methods. Many different types of glycohemoglobin assay methods were

available in the past, differing considerably with respect to the glycated com-

ponents measured, interferences, and nondiabetic range. Glycated hemoglobin

A1C (A1C) has become the preferred standard for assessing glycemic control and,

in 1996, the National Glycohemoglobin Standardization Program (NGSP) was

formed to standardize the A1C test to DCCT values. Since then, A1C measure-

ments in North America have been almost universally standardized to the DCCT

assay range.

In recent years, the International Federation of Clinical Chemistry (IFCC)

developed a new standard for A1C that results in a measurement of concentra-

tion (mmol A1C/mol HbA) rather than percent and a reference range that is

different than the DCCT standard. Although small studies had suggested this

to be the case for type 1 populations, a recent multicenter study in subjects with

type 1, type 2, and no diabetes; of multiple ethnic groups; and on multiple types

of diabetes therapies confirmed that there is a close association of A1C with the

mean blood glucose over the prior 2-3 months across the entire study population.

Hemoglobin variants have the potential to cause falsely low or high A1C

readings, especially with older assays. In 2008, only ~5% of assays done in labs

in the US give spurious results with Hb AS or A1C. A list of assays and whether

or not they are accurate in patients with hemoglobin variants can be found on

the NGSP website (http://www.ngsp.org/prog/index.html ). Additionally, patient

comorbidities affecting red blood cell turnover (hemolytic anemias, chronic kid-

ney disease) will make interpretation of the test difficult.

Utility. A properly performed A1C test provides the best available index of

chronic glucose levels. Other glycated protein molecules can be measured for

this purpose (e.g., glycated albumin or fructosamine), especially in patients with

abnormalities of red blood cell turnover, but their role in clinical practice is less

well established.

A1C testing is invaluable in identifying patients who have relatively high,

average, or near-normal levels of chronic glucose control. Discrepancies between

the A1C level and the results of SMBG may indicate that the latter is either inac-

curately performed or fabricated, or that the patient has an interfering hemoglo-

binopathy or disorder of red blood cell turnover.

Tools of Therapy

The measurement of A1C allows physician and patient to set objective goals

for therapy and to measure the efficacy of changes in therapy. The usual fre-

quency for performing this assay in type 1 diabetes should be four times per year.

A1C testing at the time of the patient’s visit with immediate results at that

time is available by several NGSP-certified instruments. Such testing allows

the patient and physician to discuss the results at that visit and make immediate

changes in treatment if needed to optimize glycemic control. Such point-of-care

testing has resulted in a 0.5- to 1-percentage point drop in the A1C value. A1C

testing by home NGSP-certified kits is also commercially available, but the value

of such testing remains to be determined.

A1C can also be used to make the diagnosis of diabetes in adults, and likely

children although this has not been confirmed. A value ≥6.5% is sufficient to

suggest diabetes, while a value of ≥5.7-6.4% suggests prediabetes.

The GlycoMark blood glucose test measures monosaccharide

1,5-anhydroglycitol in the blood, which is a specific index of elevated postmeal

glucose levels and short-term glycemic control. This test has proven useful in

pharmaceutical research, as well as in patient care, when methods are being

employed that specifically target glucose instability after meals.

OTHER MONITORING

In addition to monitoring for glycemia and A1C, patients need ongoing mon-

itoring of fasting lipid profiles, urine albumin excretion, and kidney function, as

further described in the Complications section and in the American Diabetes

Association’s Standards of Medical Care. TSH testing is recommended periodi-

cally for all patients with type 1 diabetes. Screening for celiac disease or other

auto-immune diseases may be indicated in patients with signs or symptoms.

CONCLUSION

The appropriate application of SMBG techniques provides the patient with

type 1 diabetes the opportunity to adjust therapy safely and effectively. The type

and frequency of monitoring must be individualized and will be dictated pri-

marily by the patient’s lifestyle and the intensity of insulin therapy. A1C testing

provides an objective index of long-term glucose levels and can be used to deter-

mine efficacy of treatment.

BIBLIOGRAPHY

American Diabetes Association: Tests of glycemia in diabetes (Position State-

ment). Diabetes Care 27 (Suppl. 1):S91-S93, 2004

Bergenstal RM, Tamborlane WV, Ahmann A, Buse JB, Dailey G, Davis SN,

Joyce C, Perkins BA, Welsh JB, Willi SM, Wood MA and the STAR 3 Study

Group: Effectiveness of sensor-augmented insulin-pump therapy in type 1

diabetes. N Engl J Med 363:311-320, 2010

96 Medical Management of Type 1 Diabetes

Bergenstal RM, Tamborlane WV, Ahmann A, Buse JB, Dailey G, Davis SN,

Joyce C, Perkins BA, Welsh JB, Willi SM, Wood MA and the STAR 3 Study

Group: Sensor-augmented pump therapy for A1C reduction (STAR 3)

study. Diabetes Care 34:2403-2405, 2011

Bode BW, Sabbah H, Davidson PC: What’s ahead in glucose monitoring?

Postgrad Med 109:41-44, 2001

Boland EA, Delucia M, Brandt CA, Grey MJ, Tamborlane WV: Limitations

of conventional methods of self blood glucose monitoring: lessons learned

from three days of continuous glucose monitoring (CGM) in pediatric

patients with type 1 diabetes. Diabetes 49 (Suppl. 1):397, 2000

Chase HP, Kim LM, Owen SL, MacKenzie TA, Klingensmith GJ, Murtfeldt

R, Garg SK: Continuous subcutaneous glucose monitoring in children with

type 1 diabetes. Pediatrics 107:222-226, 2001

Cheyne EH, Cavan DA, Kerr D: Performance of a continuous glucose monitor-

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Improvement in glycemic excursions with a transcutaneous, real-time con-

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monitoring at the arm. Diabetes Care 24:1303-1304, 2001

Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study

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tes Care 29:352-355, 2006

Tools of Therapy

Nielsen JK, Djurhuus CB, Gravholt CH, Carus AC, Granild-Jensen J, Orskov

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Sacks DB, Bruns DE, Goldstein DE, Maclaren NK, McDonald JM, Parrott M:

Guidelines and recommendations for laboratory analysis in the diagnosis

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18:324-329, 2002

98 Medical Management of Type 1 Diabetes

NUTRITION

he effectiveness of medical nutrition therapy (MNT) in the medical man-

agement of type 1 diabetes is well established. MNT includes a compre-

hensive assessment of the patient’s nutritional status, diabetes and health

status, weight for height or BMI, lifestyle, support systems, and willingness and

ability to make changes or initiate new behaviors. MNT is implemented in a

nutrition care plan based on individual goals negotiated with the patient and

monitoring and evaluation of goal-directed activities. Success and satisfaction

are measured by goal achievement and improved metabolic and other health

outcomes.

Managing eating is one of the most challenging aspects of diabetes self-

management and requires knowledge, time, effort, and commitment from

those involved. Although there are many other variables beside food that affect

blood glucose levels, physicians and other diabetes management care team

members often attribute poor glycemic control to a lack of dietary adherence.

In the best-case scenario, all team members are knowledgeable about nutrition

therapy and supportive of the person with diabetes who is struggling to make

lifestyle changes. Because of the complexity of nutrition issues, it is recom-

mended that a registered dietitian, knowledgeable and skilled in implement-

ing diabetes MNT, be the team member providing MNT. Patients with type

1 diabetes should be referred when diagnosed, then routinely consult with

a registered dietitian as part of the continuing medical care of their diabe-

tes. Follow-up may be appropriate every 3-6 months for children and every

6-12 months for adults.

NUTRITION RECOMMENDATIONS

The American Diabetes Association has published evidence-based nutri-

tion recommendations and interventions for diabetes. These recommendations

attempt to translate research data and clinically applicable evidence into nutri-

tion care. The Institute of Medicine’s Food and Nutrition Board of the National

Institutes of Health (NIH) has published dietary reference values for the intake

of macronutrients. This report covers dietary reference intakes (DRIs) for energy,

carbohydrates, fiber, fat, fatty acids, cholesterol, protein, and amino acids. Com-

peting with the science-based recommendations are media and commercially gen-

erated nutrition recommendations based on misinformation, opinion, and a desire

to sell a product or program. The target audience for these questionable products

and practices is often individuals with chronic disease lured by the promise of a

quick or easy solution.

The diabetes management team members must not only be knowledgeable

about science- or evidence-based recommendations, but must also be aware of the

latest health or nutrition fad or product in the marketplace. When applying scien-

tific principles and recommendations, team members will continue to focus on the

patient’s individual circumstances and preferences. The patient is the central team

member and the one who most actively manages his or her diabetes.

Tools of Therapy

The Nutrition Prescription

The “ADA Diet” as a formulated prescription of calorie and macronutrient

composition has been replaced by an individualized nutrition prescription based

on nutrition assessment and treatment goals. Specific goals of diabetes MNT

are to

n achieve and maintain

l blood glucose levels in the normal range or as close to normal as is safely

possible

l a lipid and lipoprotein profile that reduces the risk for vascular disease

l blood pressure levels in the normal range or as close to normal as is safely

possible

n prevent, or at least slow, the rate of development of the chronic compli-

cations of diabetes by modifying nutrient intake and lifestyle

n address individual nutritional needs, taking into account personal and

cultural preferences and willingness to change

Additional MNT goals for specific situations include

n for youth with type 1 diabetes, pregnant and lactating women, and older

adults, to meet the nutritional needs of these unique times in the life

cycle

n for all type 1 patients, to provide self-management training for safe con-

duct of exercise, including the prevention and treatment of hypoglyce-

mia, and diabetes treatment during acute illness

Nutrition recommendations advise that macronutrient composition and dis-

tribution be individualized to achieve desired metabolic outcomes (Table 3.5).

Table 3.5 Nutrition Recommendations: Historical Perspective

Distribution of Calories

Year

Carbohydrate (%)

Protein (%)

Fat (%)

Before 1921

Starvation diets

1921

1950

1971

1986

50-60

12-20

1994

10-20

A, B

2002

A, C

15-20*

A, B, C, D

2008

15-20

E = saturated fat < 7%

A, based on nutrition assessment; B, <10% saturated fat; C, carbohydrate and monounsaturated

fatty acids together = 60-70% energy intake; D, minimize intake of trans fatty acids.

*If renal function is normal.

100 Medical Management of Type 1 Diabetes

Integrate insulin with eating and exercise habits

Intensive therapy

Conventional therapy

Integrate

Adjust insulin

Synchronize

Eat

insulin into

to compensate

food with

consistently,

lifestyle

for lifestyle

insulin

adjust insulin

Figure 3.5 Medical nutrition therapy for type 1 diabetes.

NUTRITION THERAPY FOR TYPE 1 DIABETES

Nutritional management of type 1 diabetes requires careful attention to the

glycemic effect of foods to contain postprandial blood glucose excursions, maxi-

mize the effectiveness of exogenous insulin, and minimize hypoglycemia. MNT

also must provide for optimal growth and development of the individual and

reduce nutrition-related health risks. Although individuals with diabetes have the

same nutritional needs as individuals without diabetes, the amount and type of

food and coordination with insulin delivery directly affect blood glucose levels.

Insulin Regimens

Individuals on multiple daily injections (MDIs) of insulin or CSII therapy, i.e.,

insulin pumps, should adjust their premeal short- or rapid-acting insulin based on

the total amount of carbohydrate in their meals. Those receiving fixed daily insu-

lin doses should emphasize consistency of daily carbohydrate content at meals and

snacks. Along with the type of insulin regimen, the nutrition care plan addresses

caloric requirements, macro- and micronutrient intake, the glycemic effect of

foods and meal patterns, lifestyle, exercise, overall health status, and patient goals.

Caloric Requirements

Calories should be prescribed to achieve and maintain reasonable body weight

in all patients and normal linear growth for children. Note that reasonable weight

is defined as the weight an individual and health care provider acknowledge as

achievable and maintainable, both short and long term. This may not be the same

as traditionally defined desirable or ideal body weight. In addition to weight,

body mass index (BMI, weight in kg/height in meters squared) may also be mea-

sured with the goal of having a healthy BMI, out of the obese and overweight

range. Daily caloric requirements vary depending on age, gender, body size, and

activity patterns. Additional calories are needed to promote growth during child-

hood, adolescence, pregnancy, and lactation and for catabolic illnesses.

The Estimated Energy Requirement (EER) is defined by the Food and

Nutrition Board of the Institute of Medicine as “the dietary energy intake that

is predicted to maintain energy balance in a healthy individual of a defined age,

Tools of Therapy

101

Table 3.6 Estimating Adult Daily Energy Needs

Adults

Basal calories

20-25 kcal/kg desirable body wt

25-35 kcal/kg for catabolic illness

Add calories for activity

If sedentary

30% more calories

If moderately active

50% more calories

If strenuously active

100% more calories

Adjustments

Add 500 kcal/day to gain 1 lb/week

Subtract 500 kcal/day to lose 1 lb/week

Pregnancy: add 340 kcal/day during 2nd trimester,

452 kcal/day during 3rd trimester*

Lactation: add 330 kcal/day during 1st 6 months,

400 kcal/day during 2nd 6 months*

Adapted from Joyce M: Issues in prescribing calories. In Handbook of Diabetes Medical Nutrition

Therapy, p. 368.

*Food and Nutrition Board Institute of Medicine: Dietary Reference Intakes for Energy, Carbohydrate, Fiber,

Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients). See Bibliography.

gender, weight, height, and level of physical activity consistent with good health.”

The Food and Nutrition Board has published several tables of EER for adults

based on BMI and four physical activity levels: sedentary, low active, active, and

very active. The board also published gender- and age-based EER tables for

infants, children, and adolescents. These tables are available on the Internet from

the National Academies Press website (see Resources for Professionals). Several

other methods for estimating caloric requirements are available, including the

Harris-Benedict or World Health Organization equations, which compute calo-

ries for basal or resting energy expenditure (REE) and then add activity calories

to the basal requirement. Simple methods for routine use are outlined in Table

3.6. Accurate records of food intake offer another means for estimating energy

requirements and provide useful information on food preferences and eating

patterns. Adjustments in caloric intake will need to be made to promote growth,

weight gain, weight loss, or weight maintenance. In addition to meeting energy

requirements, the caloric prescription promotes a consistency in daily food intake

that is helpful in managing type 1 diabetes.

Macronutrients

In general, recommendations for the macronutrient composition of the meal

plan for diabetes correspond to guidelines for healthy eating for all Americans.

The composition and distribution will be guided by the individual’s needs and

preferences.

Carbohydrate

The primary role of carbohydrates (sugars and starches) is to provide energy

to cells in the body. The RDA for carbohydrate is set at 130 g/day for adults and

102 Medical Management of Type 1 Diabetes

Table 3.7 Classification of Carbohydrates

Class

Subgroup

Components

Sugars

Monosaccharides

Glucose, galactose, fructose

Disaccharides

Sucrose, lactose

Polyols

Sorbitol, mannitol, xylitol

Polysaccharides

Starch

Amylose, amylopectin, modified starches

Nonstarch

Cellulose, hemicellulose, pectins,

polysaccharides (fiber)

hydrocolloids

children and is based on the average minimum amount of glucose utilized by the

brain.

Carbohydrate Classification

Carbohydrates are divided into categories based on the number of sugar

units. The categories of greatest interest in diabetes care and education are sug-

ars (monosaccharides, disaccharides, and polyols) and polysaccharides (starches

and nonstarch polysaccharides [fiber]) (Table 3.7). The terms “complex carbohy-

drates” and “simple sugars” are no longer used. Intrinsic sugars are sugars that

are present within the cell walls of plants (naturally occurring), whereas extrinsic

sugars are those that are typically added to foods. Added sugars are defined as

sugars and syrups that are added to foods during production and do not include

naturally occurring sugars such as lactose in milk or fructose in fruits. Foods and

beverages with a high added sugar content include soft drinks, cookies, cakes,

pastries, and candy. These foods and beverages have lower micronutrient densi-

ties compared to those that are major sources of naturally occurring sugars. Cur-

rent US food labels do not distinguish between sugars naturally present in foods

and added sugars. Traditionally, sugars, particularly sucrose, have been restricted

in diets for individuals with diabetes. However, studies show that this restriction

is not warranted metabolically. The USDA Food Guide Pyramid guidelines allow

for added sugars as part of discretionary calories once food is consumed from

nutrient-dense food groups. Generally speaking, this would be <10% of calo-

ries for most calorie levels. Carbohydrates providing essential nutrients should

receive first priority in food choices over selecting foods and beverages high in

added sugars and low in nutrient density.

Healthy carbohydrates. Foods containing carbohydrate from whole grains,

fruits, vegetables, legumes and dry beans, and fat-free or low-fat milk are impor-

tant sources of vitamins, minerals, phytochemicals, and fiber and are preferred

choices for carbohydrate-containing foods. Healthy eating programs such as

MyPlate from the USDA, Fruits and Veggies, More Matters (previously Five a

Day) program, and the Dietary Approaches to Stop Hypertension (DASH) diet

Tools of Therapy

103

encourage increased intake of fruits and vegetables, whole grains, and low-fat

milk.

Glycemic effect of carbohydrate. The American Diabetes Association’s posi-

tion states that the total amount of carbohydrate in meals and snacks is usually

the primary determinant of postprandial response, but the type of carbohydrate

may also affect this response. A key strategy in achieving glycemic control is

by monitoring carbohydrate, whether by carbohydrate counting, exchanges, or

experienced-based estimation. The use of the glycemic index and load may pro-

vide a modest additional benefit over that observed when total carbohydrate is

considered alone.

Individuals using MDI or CSII therapy should adjust premeal insulin doses

based on the total carbohydrate content of the meal. Those on fixed doses of

insulin should be consistent with their carbohydrate intake. There is widespread

interest and controversy surrounding the concepts of glycemic index and glyce-

mic load. See Fig. 3.6 and Fig. 3.7 for definitions.

Glycemic index. Glycemic index (GI) is a concept and meal-planning

approach based on published tables ranking carbohydrate foods according to gly-

cemic response (Fig. 3.6). The tables propose that, per gram of carbohydrate,

foods with a high GI produce a higher peak in postprandial blood glucose and a

greater overall glucose response during the first 2-3 h after consumption than do

foods with a low GI. The International Table of Glycemic Index and Glycemic

Load Values: 2002 contains 1,300 data entries representing 750 different types of

foods tested. Study subjects included “healthy” volunteers and those with type 1

or type 2 diabetes. Type 1 diabetes subjects participated in the study of 17% of

the foods included in the table.

“The glycemic index is a classification proposed to quantify the relative blood glucose

response to carbohydrate-containing foods. It is defined as the area under the curve for

the increase in blood glucose after the ingestion of a set amount of carbohydrate in an

individual food (e.g., 50 g) in the 2-h postingestion period as compared with ingestion of

the same amount of carbohydrate from a reference food (white bread or glucose) tested in

the same individual under the same conditions using the initial blood glucose concentra-

tion as a baseline.”

Figure 3.6 Glycemic Index: Institute of Medicine’s Food and Nutrition

Board definition.

“Thus, the GL of a typical serving of food is the product of the amount of available car-

bohydrate in that serving and the GI of the food.” The GL values in the tables were cal-

culated “by multiplying the amount of carbohydrate contained in a specified serving size

of the food by the GI value of that food (with the use of glucose as the reference food),

which was then divided by 100.” Because portion sizes vary from country to country,

researchers and health professionals are advised to calculate their own GL data by using

appropriate serving sizes and carbohydrate composition data.

Figure 3.7 Glycemic load (GL): International Table of Glycemic Index and

Glycemic Load Values: 2002 definition.

104 Medical Management of Type 1 Diabetes

Table 3.8 Factors Affecting the Rate of Digestibility and Glycemic

Response

Factors inherent in a food

Grain, particle size

Amylose-amylopectin (starch) ratio

Fiber content

Enzyme inhibitors

Physical interaction with fat or protein

within a food

Degree of ripeness in fruit

Factors related to preparation

State of hydration

Raw vs. cooked

Amount of food processing

Factors related to consumption

Addition of protein, fat, other foods

Acidity of a meal

Preceding meal

Time of day

Palatability

Duration of the meal

Rate of gastric emptying

The concept of GI seemed straightforward when it was first introduced as a

research tool in the 1980s, but the use of GI in preventing and treating disease

has created much controversy. Proponents of GI support its role in treating and

preventing chronic disease, including diabetes, obesity, coronary heart disease,

and cancer. Critics of GI point out flaws in epidemiologic studies cited in support

of GI as a public health tool. Additional concerns are related to the utility of the

tables as a tool for nutritional management. Within each food category, there is

wide variability; values can vary as much as fivefold, depending on the food form,

study setting, and other factors. In earlier studies, cooked carrots received a GI

rating of 92 ± 20, whereas in more recent studies, they are rated at 32 ± 5. Many

factors affect the glycemic response, including variation in the food and its prepa-

ration and the circumstances under which it is ingested (Table 3.8). Additionally,

variability within and between subjects is large.

Glycemic load. The portion sizes for many of the foods studied for GI were

not realistic or usual. To obtain 50 g carbohydrate from carrots, almost five cups

of cooked carrots would need to be ingested. The concept of glycemic load (GL)

was introduced to take into account the amount of carbohydrate in a usual serving

of a particular food. The GL is calculated using the average GI of the particular

food, multiplied by the grams of carbohydrate available in a typical serving of that

food (Fig. 3.4). GL has been calculated for the foods listed in the International

Tools of Therapy

105

Table. Concerns about GL are based on the use of imprecise values multiplied to

give yet another imprecise number. To use GI, or GL, as a meal-planning tool,

one would select foods with low or medium GI versus those with a high GI or,

if consuming high-GI foods, also select low-GI foods for balance. The assump-

tion is that the higher the GI or GL, the greater the expected elevation in blood

glucose and insulin requirements.

Using GI for meal planning. The American Diabetes Association position

is that GI adds another level of complexity to meal planning without scientific

evidence to recommend its use as a primary strategy. However, a recent meta-

analysis of low glycemic index or low glycemic load diets in diabetes involving 11

randomized controlled trials and 402 participants with poorly controlled diabetes

showed that compared to higher glycemic diets there was a significant decrease

in A1C by -0.5% (with either parallel or crossover studies). In addition, the pro-

portion of participants with more than 15 episodes of hyperglycemia per month

was less and there was no increase in hypoglycemia, morbidity, or costs. This

suggests that people with type 1 diabetes may find value in identifying foods and

circumstances to determine their own personal GI of preferred and frequently

used foods and meals. Based on their unique response, they can develop strategies

to adjust meal-related insulin accordingly. The starting point is to match premeal

insulin doses to the total carbohydrate content of the meal.

Resistant starch. There are no published long-term studies proving benefit

from use of resistant starch in subjects with diabetes.

Nutritive Sweeteners

Sucrose. Sucrose restriction in the diet for diabetes cannot be justified on

the basis of its glycemic effect. Sucrose can be included in diets of people with

diabetes by making appropriate substitutions for other carbohydrate sources to

maintain consistent carbohydrate intake. If the sucrose-containing food is added

as an extra, it can be covered with additional short- or rapid-acting insulin. How-

ever, patients should consider the potential for a decrease in nutrient value and

an increase in fat intake and calories that often accompanies sucrose-containing

foods.

Fructose. Fructose has a low glycemic effect, which suggests that it could

be a useful sweetener for individuals with diabetes. Large amounts of fructose,

however, can have an adverse effect on blood lipids. Like other sugars, fruc-

tose provides 4 cal/g and in general does not offer strong advantages over other

sweeteners.

Natural sweetener. Fruit juice, honey, molasses, corn syrup, and other natural

sweeteners require the same considerations as sucrose. They contribute 4 cal/g

and need to be counted as carbohydrate in meal planning.

Sugar alcohols. Sugar alcohols (e.g., sorbitol) and hydrogenated starch

hydrolysates have less of a glycemic effect than sucrose and yield about

2 cal/g on average. Some individuals report gastric discomfort after eating foods sweet-

ened with these products, and consumption of large quantities can cause diarrhea.

106 Medical Management of Type 1 Diabetes

Nonnutritive Sweeteners

Nonnutritive sweeteners available in the US include acesulfame potassium,

aspartame, neotame, saccharin, stevia, and sucralose. The FDA determines an

acceptable daily intake (ADI) for products it approves that is defined as a safe

amount for daily consumption over a lifetime. The ADI includes a 100-fold safety

factor and greatly exceeds average consumption levels. All FDA-approved sweet-

eners can be used by individuals with diabetes, including pregnant women. How-

ever, moderation is often recommended.

Fiber

Dietary fiber appears to benefit overall bowel health, including prevention

and treatment of constipation and possible prevention of colon cancer. Soluble

fiber in large amounts has been shown to be effective in reducing total and LDL

cholesterol levels in diabetic and nondiabetic subjects. The beneficial effect of

soluble dietary fiber on glycemic control, although intuitively attractive, is dif-

ficult to substantiate. An overall benefit to blood glucose control from dietary

fiber has not been established and may require large amounts (>50 g fiber) to

achieve a significant effect. The Food and Nutrition Board of the NIH, for the

first time, has indicated an adequate intake (AI) for fiber (Table 3.9). The Choose

Your Foods: Exchange Lists for Meal Planning’s starch, vegetable, fruit, and plant-

based protein lists identify foods that provide more than 3 g of dietary fiber per

serving.

Protein

Daily requirements. The RDA for protein is 0.8 g/kg/day of high-quality

protein for adults, which corresponds to ~10% of calories. This is lower than the

usual protein intake of 15-20% of calories consumed by adults in the general US

population. The long-term effects of diets with 20% of energy as protein on renal

function have not been determined. Protein requirements for children range from

1.5 g/kg/day for infants to 0.85 g/kg/day for adolescent males through 18 years of

age. Some patients who are interested in strength training and muscle develop-

ment are advised by trainers, coaches, and others to take large amounts of protein

or amino acids, often in powdered form, to build muscle. When patients indicate

an interest in strength training activities, diabetes clinicians must be prepared

Table 3.9 Adequate Intake for Total Fiber

Men

Women

Adults aged <50 years

38 g

25 g

Adults aged ≥50 years

30 g

21 g

Adapted from Food and Nutrition Board Institute of Medicine: Dietary, Reference Intakes for Energy,

Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients). See

Bibliography.

Tools of Therapy

107

to discuss with them safe amounts of protein intake for their individual kidney

function status.

Protein and nephropathy. There is no evidence to suggest that the usual

intake of protein needs modification if renal function is normal. In patients with

diabetic nephropathy, reduction of dietary protein to 0.8-1.0 g/kg/day for people

with earlier stages of chronic kidney disease and to 0.8 g/kg/day in the later stages

of CKD may improve measures of renal function.

Protein and insulin requirements. Meal doses of insulin are calculated based

on the carbohydrate content of the meal, with the assumption that the basal insu-

lin will cover the attenuated glycemic effects of the protein in the meal. The addi-

tion of larger than usual amounts of protein to meals may require a small amount

of additional insulin 3-5 h following the meal. Individuals using CSII may use

extended delivery of meal bolus insulin for this type of meal. A dual-wave bolus

can deliver part of the meal bolus before the meal and the remainder over 2-4 h

following the meal.

Fat

The 80-85% of daily calories not allocated to dietary protein are distributed

between carbohydrate and fat sources. Saturated fat and trans unsaturated fatty

acids (trans fats) are highly atherogenic and have a greater impact on serum cho-

lesterol than dietary cholesterol. Because diabetes is an independent risk factor

for cardiovascular disease, the ADA recommends restricting saturated fat intake

to <7% of calories and that trans fats be minimized. Dietary cholesterol intake

should be <200 mg/day. Content of the diet from monounsaturated and polyun-

saturated fats should be individualized to reach goals.

Foods that contain omega-3 fatty acids have cardioprotective effects; the ADA

recommends that people with diabetes (as is true of the general population) eat 2-3

servings per week of foods providing omega-3 polyunsaturated fat, such as fish.

Alcohol

Most adults with type 1 diabetes may drink alcohol in moderation if they so

choose. Exceptions include individuals whose blood glucose is out of control,

those with elevated blood triglycerides, and pregnant women. Daily intake should

be limited to one drink for women and two drinks for men. One drink is 12 oz

beer, 5 oz wine, or 1.5 oz 80-proof distilled spirits. Each drink contains 15 g

alcohol.

In addition to the precautions regarding alcohol use that apply to the general

public, people with type 1 diabetes risk alcohol-induced hypoglycemia for up to

24 h after ingestion, especially if meals are skipped or delayed or during fasting.

Therefore, alcoholic beverages should be ingested with food. If the patient is

overweight and consumes alcohol on a regular basis, adjustments to the meal plan

to account for calories from alcohol (7 cal/g) without increasing risk for hypogly-

cemia should be considered. A reduction in fat (9 cal/g) intake is preferable to a

reduction in carbohydrate intake, because of the hypoglycemia implications, to

offset calories consumed in an alcoholic beverage.

108 Medical Management of Type 1 Diabetes

Micronutrients

Sodium and hypertension. People differ greatly in their sensitivity to sodium

and its effect on blood pressure. The recommendation for people with normo-

tension is a reduced sodium intake of ≤2,300 mg/day sodium 1500 mg/day and

a diet high in fruits, vegetables, and low-fat dairy products. For individuals with

symptomatic heart failure, reducing sodium to ≤2,000 mg/day may help reduce

symptoms. Sodium intake can be minimized by reducing the use of table salt,

processed and convenience foods, and fast foods. Choose Your Foods: Exchange Lists

for Meal Planning highlights foods with a sodium content >480 mg/serving. The

Nutrition Facts panel on food labels provides useful information by indicating,

for a single serving, the amount of sodium in milligrams and the percent of the

daily value (the % of 2,400 mg). A consumer may wish to reconsider use of a food

containing >25% of the daily value.

Potassium. Individuals taking diuretics may experience a loss of potassium

sufficient to warrant supplementation. Potassium restriction may be required if

hyperkalemia occurs in patients with renal insufficiency or in those taking angiotensin-

converting enzyme inhibitors or angiotensin receptor blockers.

Magnesium. Magnesium deficiency can be easily detected and treated. The

deficiency may occur as a result of poorly controlled diabetes and the accompany-

ing urinary loss.

Calcium. The Food and Nutrition Board of the Institute of Medicine has

established AIs for calcium based on age (Table 3.10). The values are the same for

males and females. Because of enhanced absorption of calcium during pregnancy

and lactation, calcium requirements are similar to the nonpregnant and nonlac-

tating state and are based on age.

Vitamin and mineral supplementation. At this time, there is no clear evi-

dence that vitamin and mineral requirements of individuals with type 1 diabe-

tes are different from those of other healthy people. If a nutrition assessment

reveals a deficiency, individuals should be counseled on how to adjust food

intake to meet these needs. If they are unable to do so, supplements should be

recommended. When caloric intake is ≤1,200 cal/day, use of a multivitamin

and mineral supplement should be advised. Several conditions may create a

deficiency in one or more micronutrients that would warrant supplementation.

These include poor diabetes control, celiac (fat soluble vitamins), use of diuret-

ics, critical care environments, medications that alter micronutrient metabo-

lism, strict vegetarian diets, nutritional intakes that do not meet established

RDAs or AIs, pregnancy, and lactation. Pregnancy increases requirements for

folate and iron.

Herbal and botanical supplements. Many people who balk at taking pre-

scription or over-the-counter medications view herbal and botanical products

as a safe and natural alternative or adjunct to their diabetes management plan.

Very few randomized, clinical trials have examined the safety and efficacy of these

products, especially for people with diabetes. Herbal and botanical supplements,

sports supplements, vitamins, minerals and other specialty products represent a

Tools of Therapy

109

Table 3.10 Adequate Intake for Calcium

Age

Adequate Intake (mg/day)

0-6 months

210

7-12 months

270

1-3 years

700

4-8 years

1,000

9-18 years

1,300

19-50 years

1,000

≥51 years

1,200

Dietary Reference Intakes for Calcium and Vitamin D (2011, Food and Nutrition Board, Institute of Medi-

cine, National Academies, www.nap.edu)

$22 billion industry in the US. The 1994 Dietary Supplement Health and Educa-

tion Act (DSHEA) changed the regulation of dietary supplements and associated

label claims. DSHEA places the burden of proof of unsafe or adulterated products

or of false or misleading labeling on the FDA rather than on the manufacturer.

However, DSHEA restricts the FDA in regulation of these products. The Fed-

eral Trade Commission regulates the advertising of dietary supplements and has

taken action against sponsors of false and misleading information. Until proven

otherwise, consumers have no assurance that a product contains what the label

says it does or that it is free from harmful contaminants. Some herbal prepara-

tions have been found to surreptitiously contain pharmaceutical agents that pro-

duce hypoglycemia. Health care providers should ask whether their patients are

using these products, as many patients do not voluntarily share this information.

While providing individualized, science-based information, it is also important

to be sensitive to the patient’s decisions to use products that might be considered

questionable. The FDA Center for Food Safety & Applied Nutrition and the

National Institute of Health Office of Dietary Supplements can provide reliable

information about many of these products (see Resources for Patient Education,

page 119).

ADDITIONAL NUTRITION CONSIDERATIONS

Sick-Day Management

Individuals with type 1 diabetes must be educated to manage brief periods

when they cannot ingest solid foods. They must understand the need to con-

tinue insulin therapy and carbohydrate consumption. Fruit juices and sugar-

containing soda, sports drinks, or gelatin can replace the usual carbohydrate

in the meal plan. Frequent intermittent intake of small amounts of these foods

and beverages helps to provide fluids and energy and helps to avoid hypoglyce-

mia. Individuals should also be taught the value of ingesting fluids containing

sodium and potassium (e.g., vegetable and fruit juices and broths) to help replace

110 Medical Management of Type 1 Diabetes

electrolytes lost from diarrhea and vomiting. The usual meal plan should be rein-

troduced gradually (see Table 2.7, page 47).

Growth Years

For infants, children, and adolescents, height and weight data can be plotted

on standardized growth grids. The caloric prescription for children with diabe-

tes should include adequate calories for growth and development. Poor diabetes

control during the growth years can contribute to failure to attain height poten-

tial. During these years, it is helpful to schedule visits with the dietitian every

3-6 months to adjust calories and other nutrients and to account for changes in

food preferences and habits. Parents of infants and young children with diabetes

may need frequent nutrition counseling to deal with eating challenges common

to children that present particular difficulty when coupled with type 1 diabetes.

Pregnancy

The 2005 RDA for pregnant women sets increased calorie requirements at

340 kcal during the 2nd trimester and 452 kcal during the 3rd trimester. The

RDA for protein during pregnancy is 1.1 g/kg, or approximately an additional

25 g/day protein. The 1990 National Academy of Sciences recommendations

for optimum weight gain for pregnant women are based on prepregnancy BMI

(Table 3.11). These guidelines anticipate delivery of babies weighing 3-4 kg at

term. The 1998 Food and Nutrition Board publication recommends that, to

reduce the risk of neural tube defects for women capable of becoming pregnant,

400 µg folic acid should be taken daily from fortified foods, supplements, or

both in addition to consuming folate from a varied diet. Therefore, prescribing

a multivitamin plus up to 400 µg/day folate from preconception through the 1st

trimester is recommended. The RDA for iron during pregnancy is 27 mg/day.

Assessment of nutritional status and dietary intake should guide prescription

of supplements. Because of the additional metabolic stress of diabetes on preg-

nancy, nutritional guidelines need to be individualized for each pregnant diabe-

tes patient to promote optimal blood glucose levels and appropriate maternal

and fetal weight gain.

A plan of three meals and three to four snacks will help patients minimize

blood glucose excursions and facilitate tight glycemic control. If there is morning

ketosis with normal blood glucose levels, the amount of food in the pre-bedtime

snack can be increased or a snack at 3:00 a.m. considered. In the 1st trimester,

hyperemesis may be a problem. A very liberal meal plan allowing the patient to

eat whatever is tolerated can be helpful. Insulin dosage should be adjusted to

allow for minimum food intake at critical points during the day.

Lactation

The protein RDA for lactation is an additional 25 g/day above pre-pregnancy

requirements. Additional EER for lactation is based on a milk energy output of

330 kcal/day in the first 6 months and 400 kcal/day in the second 6 months. Many

women with diabetes report wide swings in blood glucose levels while they are

Tools of Therapy

111

Table 3.11 Recommendations for Total and Rate of Weight Gain

during Pregnancy, by Prepregnancy BMI

Total weight gain

Rates of weight gain*

2nd and 3rd trimester

Mean (range) in

Mean (range)

Range in kg Range in lbs

kg/ week

in lbs/week

Prepregnancy BMI

Underweight

12.5-18

28-40

0.51 (0.44-0.58)

1 (1-1.3)

(<18.5 kg/m²)

Normal weight

11.5-16

25-35

0.42 (0.35-0.50)

1 (0.8-1)

(18.5-24.9 kg/m²)

Overweight

7-11.5

15-25

0.28 (0.23-0.33)

0.6 (0.5-0.7)

(25.0-29.9 kg/m²)

Obese (≥30.0 kg/m²)

5-9

11-20

0.22 (0.17-0.27)

0.5 (0.4-0.6)

BMI: body mass index.

* Calculations assume a 0.5-2 kg (1.1-4.4 lbs) weight gain in the first trimester.

From Weight Gain During Pregnancy: Reexamining the Guidelines. Institute of Medicine (US) and Na-

tional Research Council (US) Committee to Reexamine IOM Pregnancy Weight Guidelines, Rasmussen

KM, Yaktine AL (Eds), National Academies Press (US), The National Academies Collection: Reports

funded by National Institutes of Health, Washington (DC) 2009. Available at http://www.nap.edu/cata-

breast-feeding, which may be related to the amount of milk produced and the

frequency of feedings. Continuing the pregnancy meal pattern of three meals and

three to four snacks may help prevent hypoglycemia and decrease the need for

additional insulin to cover the extra calories.

Obesity Management

People with type 1 diabetes may gain excessive weight for several reasons:

n overinsulinization

n frequent and inappropriate treatment of insulin reactions

n efforts to avoid insulin reactions with the use of extra food

n failure to decrease caloric intake to compensate for decreased urinary

caloric loss with improved glucose control

n general overemphasis on food intake

Individuals and parents of children with diabetes should be advised about

the consequences of obesity on general health. Individuals with diabetes who are

attempting to lose weight should avoid fad diets that promote inappropriate food

combinations or omissions and rapid weight loss, because dehydration, fluid and

electrolyte imbalances, and starvation ketosis may result. Weight loss programs

for individuals with type 1 diabetes must include advice about insulin dose adjust-

ment, careful monitoring of diabetes control, and realistic weight loss goals.

112 Medical Management of Type 1 Diabetes

The American Diabetes Association advises that either low-carbohydrate

low-fat or Mediterranean style calorie-restricted diets may be effective for

short-term weight loss (up to 2 years, the duration of comparative studies).

If patients are following a low-carbohydrate diet, clinicians should monitor

lipid profiles, because these diets can raise LDL cholesterol. Because low-

carbohydrate diets may be high in protein, those with nephropathy should be

counseled about appropriate protein intake, and renal function should be moni-

tored. Patients using I:C can adjust their prandial insulin downward to account

for the lower carbohydrate intake. Patients who lose weight from either type of

diet are likely to need changes in their I:C due to the effects of weight loss on

insulin sensitivity.

To enable the overweight or obese patient with type 1 diabetes to alter his or her

eating, motivational interviewing can be employed to initiate behavior change. Moti-

vational interviewing is a patient-centered method for enhancing intrinsic motivation

to change by exploring and resolving ambivalence; however, the basic tenet is that the

patient must be ready to change, and that desire must emanate from within, and not

be thrust upon the patient by a member of the health care team.

Long-term maintenance of weight loss is a challenge. Strategies for successful

weight management are emerging from the National Weight Control Registry

(NWCR), a prospective study of individuals age ≥ 18 years who have successfully

maintained a 30-lb weight loss for a minimum of 1 year. The NWCR, a collab-

orative effort between the University of Colorado Health Sciences Center and

the University of Pittsburgh School of Medicine, currently includes over 5,000

individuals and offers the opportunity to study the eating and exercise habits of

successful weight loss maintainers (www.nwcr.ws ). The average registrant was

overweight as a child (66%), has a family history of obesity, and has a lifetime

average gain and loss of 271 lb. Half followed a formal weight loss program.

Additional characteristics of the average registrant include:

n has a resting metabolic rate equal to the rate of a nondieting counterpart

in the same weight range

n has lost 66 lb and kept it off for 5.5 years

n takes in an average of 1,400 calories/day (macronutrient composition is

49% carbohydrate, 22% protein, and 29% fat)

n exercises, on average, about 1 h per day

n walks for exercise

n eats breakfast every day

NWCR registrants indicate that weight loss maintenance becomes easier over

time. Additional strategies used by these registrants include keeping many healthy

foods in the house (87%), keeping records of food intake or exercise (43%), and

buying books or magazines related to nutrition or exercise (74%).

Disordered Eating

An increasing number of children, adolescents, and adults in the general

population appear to be affected with anorexia nervosa, bulimia, or a combi-

nation of the two. Disordered eating in type 1 diabetes is more common than

Tools of Therapy

113

previously thought. A meta-analysis evaluating the prevalence of eating disor-

ders in type 1 diabetes in 748 and 1,587 female subjects with and without dia-

betes, respectively, showed the prevalence of anorexia nervosa was not different

between controls and subjects with type 1 diabetes. However, the prevalence of

bulimia nervosa and bulimia plus anorexia combined was significantly higher

in patients with diabetes. Type 1 diabetes complicated by an eating disorder is

very difficult to manage because of erratic eating patterns and purging behav-

iors such as vomiting, laxative abuse, or excessive exercise. A purging behavior

unique to type 1 diabetes is self-induced glycosuria, achieved by insulin omis-

sion. These destructive behaviors can lead to recurrent diabetic ketoacidosis

and early development of long-term complications. Risk factors for disordered

eating in girls and women with type 1 diabetes include higher BMI, increased

body weight and shape dissatisfaction, low self-esteem and depression, and

dietary restraint. Recognition and treatment are critical, along with referral to

experienced medical, psychological, and nutrition counselors (see Resources for

Patient Education, page 119).

THE PROCESS OF MEDICAL NUTRITION THERAPY

The process of MNT begins with a comprehensive assessment of the patient’s

diabetes status and nutritional status. Following the assessment, the intervention

includes collaboration on setting metabolic and self-care goals determined by

patient and dietitian as priorities and a plan for action. Achievement of goals

will be monitored by ongoing communication between the patient and dietitian.

Follow-up visits will provide opportunities to evaluate progress, identify barri-

ers to success, solve problems, and make necessary changes in the plan of care.

Although the dietitian is the primary provider of MNT, this component of dia-

betes management must be integrated into the care provided by all members of

the core team. Coordination of this effort is supported by concise and accurate

documentation, communication among team members, and consistency of dia-

betes and nutrition messages provided to the patient.

Assessment

A comprehensive nutrition assessment (Table 3.12) contains components of

the medical evaluation and the education assessment for overall diabetes educa-

tion needs. Recognizing that the other members of the patient’s diabetes care

team need similar information should encourage communication among clini-

cians, collaboration on treatment goals, and consistency of messages provided to

the patient.

Goal-Setting

Specific goals for MNT are identified through the nutrition assessment.

These goals must correspond with the overall treatment goals for the individual

and must agree with the patient’s personal goals for therapy. Goal-setting is often

a negotiation process involving clinicians and the patient. Goals should be real-

istic and specific.

114 Medical Management of Type 1 Diabetes

Table 3.12 Nutrition Assessment

Clinical Data

n Type of carbohydrate, protein, and fat

n Use of vitamins, minerals, and herbal and

n Height, weight, BMI

botanical products

n Body frame

n Reasonable weight

Social History

n Blood pressure

n Daily schedule

n Family history

n Family relationships

n Blood glucose and lipids

n Friends—social support

n A1C

n Finances and living environment

n Abnormal laboratory findings

Education—learning style

Nutrition History

n Self-efficacy

n Usual food intake

Diabetes and Health Status

n Attitudes toward nutrition and health

n Duration of diabetes

n Previous nutrition education and

n Insulin regimen

outcomes

n Hypoglycemia treatment and history

n Cultural food practices

n Diabetes knowledge and skills

n Physical activity

n Complications history and current

n Allergies and intolerances

status

Nutrient Intake

n Other medications

n Smoking

n Overall nutritional adequacy

n Alcohol

n Caloric intake

n Nutrient distribution

Nutrition Care Plan

The meal plan for type 1 diabetes is directed by the insulin deficiency that

characterizes the condition. Food intake and insulin regimens must be coordi-

nated to accommodate the patient’s food preferences and lifestyle while achieving

goal glucose levels as closely as is safely possible. Fortunately, SMBG, basal-bolus

insulin regimens, and CSII support this coordination effort. Specific strategies

for nutritional management of type 1 diabetes are to

n integrate insulin therapy with an individual’s food and physical activity

preferences

n base the food plan on assessment of appetite, preferred foods, and usual

eating and exercise habits

n use information from SMBG, CGM, insulin, food, and physical activity

records and uploads to make adjustments in food intake or insulin dose to

achieve target glucose levels

n modify caloric and nutrient composition of the food plan as appropriate

to achieve metabolic and weight goals and for different stages of the life

cycle

The individualized self-management plan should also reflect the patient’s

lifestyle, exercise patterns, and resources. Important considerations include

Tools of Therapy

115

n daily schedule (weekday and weekend), travel to and from work or school,

during work/school, recreational and social activities

n individual’s and family’s eating patterns, including usual time and size of

meals, where meals are eaten, food preferences, social habits, and cultural

customs

n availability of food at home, school, or work; and food budget

n facilities and equipment for preparation and storage of food

Evaluation

The effectiveness of the nutrition treatment plan is evaluated by outcomes

specifically related to the goals of therapy. Outcomes would include metabolic

and behavior change measures.

Practice Guidelines for MNT of Type 1 Diabetes

Practice guidelines offer a systematic approach to disease management

designed to increase assurance that desired outcomes will be achieved. Nutrition

practice guidelines for type 1 and type 2 diabetes were developed using criteria set

forth by the Institute of Medicine. In field tests of the nutrition practice guide-

lines for type 1 diabetes, practice guideline patients achieved greater reduction in

A1C than usual care patients. These guidelines are available from the Academy of

Nutrition and Dietetics (see Resources for Patient Education, page 119).

PRACTICAL APPROACHES TO NUTRITION COUNSELING

Pattern Management

SMBG, CGM, insulin, food, and physical activity records and uploads pro-

vide patients and clinicians an evaluation mechanism that can be used to closely

examine the effectiveness of the treatment regimen and to make adjustments to

improve glycemic control. Finding and interpreting blood glucose patterns leads

to possible changes in either the amount or timing of insulin, food, or physical

activity.

Carbohydrate Counting for Intensive Insulin Therapy

Carbohydrate counting is a meal planning approach that focuses on carbohy-

drate as the primary nutrient affecting postprandial glycemic response. Carbohy-

drate counting can be used at basic or advanced levels depending on the interest

and skills of the individual.

Basic carbohydrate counting. Carbohydrate counting can be used at a basic

level by patients whose goals include consistency of carbohydrate intake to

support improved glycemic control. Patients first learn to estimate how much

carbohydrate is in their meals and snacks by becoming familiar with reference

amounts of foods similar to the exchange lists or other published carbohydrate

116 Medical Management of Type 1 Diabetes

food lists. Other skills include reading food labels accurately for carbohydrate

values and estimating carbohydrate amounts in combination foods such as pizza

and in restaurants or meals prepared by others. A person must be willing to

spend time and effort learning and practicing measuring and weighing foods,

reading food labels, and using reference books to develop the skills necessary

to accurately estimate carbohydrate amounts in portions usually eaten. These

skills require moderate levels of literacy and numeracy. Nutrient databases are

available on the Internet and as software for loading into personal computers or

personal digital assistants.

Advanced carbohydrate counting. Individuals on intensive insulin therapy,

either basal-bolus regimens or CSII, can learn to match their premeal insulin to

their carbohydrate foods using an individualized insulin-to-carbohydrate ratio.

Patients striving for tight glucose control while maintaining flexibility in meals

and snacks are candidates for using this counting method.

The insulin-to-carbohydrate ratio is determined for individuals based on

records of SMBG, CGM, insulin doses, food intake, and physical activity. The

ratio is based on the amount of short- or rapid-acting insulin needed to cover a

specific amount of carbohydrate to achieve postprandial glucose targets. For exam-

ple, a patient uses 1 unit rapid-acting insulin for every 10 g carbohydrate eaten to

achieve a specific blood glucose target 2 h postprandially. Therefore, this person

has an insulin-to-carbohydrate ratio of 1:10, i.e., 1 unit insulin covers 10 g carbo-

hydrate. To adjust insulin for varying amounts of carbohydrate, divide the total

grams of carbohydrate to be consumed by the insulin-to-carbohydrate ratio. A meal

with 100 g carbohydrate would require 10 units of premeal insulin (100 g divided

by 10 = 10 units insulin). Some formulas for initially calculating insulin-to-

carbohydrate ratio include weight and total daily insulin dose as part of the equation

(e.g., 450 divided by total daily dose; see Optimizing Blood Glucose Control, page 74).

An absolute prerequisite for insulin-to-carbohydrate ratio use is that the

patient must already be extremely well versed in carbohydrate counting. The

insulin-to-carbohydrate ratio’s effectiveness depends on the patient’s ability to

accurately estimate carbohydrate amounts that can be covered by insulin. Mis-

calculation of consumed carbohydrate will result in taking too much or too little

insulin. Time, effort, and practice are needed to become proficient enough in

carbohydrate counting to use it safely and effectively in insulin dose calculation

and adjustment.

Individuals using insulin-to-carbohydrate ratios also need to consider other

factors that affect glycemic response and be aware that they may need to adjust

timing of insulin delivery as well as amount of insulin for specific situations. For

example, high-fat meals can delay stomach emptying and may require delivery of

a divided dose of insulin, such as part of the dose before and part after the meal.

CSII allows delivery of extended boluses that help to accommodate this type of

insulin delivery.

Nutrition Self-Management Tools

Meal planning tools, such as the Basic Carbohydrate Counting, Match Your

Carb to Your Insulin, Choose Your Foods: Exchange Lists for Diabetes, or its

Tools of Therapy

117

simplified version, Healthy Food Choices, can be used to guide patients in imple-

menting their nutrition management plan. These tools are available from the

American Diabetes Association and the Academy of Nutrition and Dietetics.

These associations also offer nutrition education materials related to several

ethnic and regional food practices. The American Diabetes Association has

published a variety of cookbooks and meal planning books, and in addition has

nutrition resources for patients on its website, www.diabetes.org. A meal plan-

ning resource should be selected that is appropriate for the patient’s lifestyle,

reading level, culture, and intensity of diabetes management.

Staged Nutrition Counseling

Eating habits are not easy to change. For the person with type 1 diabetes,

the need to balance food intake and activity, the potential for hypoglycemia,

and the psychological stress of managing a chronic disease make changing food

habits even more difficult. Nutrition counseling should be provided in stages to

allow the patient time to absorb information, try out self-management skills, and

test the nutrition plan in daily living. Staged nutrition counseling also provides

an opportunity to evaluate the effectiveness of the treatment plan and to make

modifications to improve diabetes control. MNT is a lifetime treatment of diabe-

tes. Therefore, nutrition counseling must be included in the ongoing care of the

patient with type 1 diabetes.

CONCLUSION

Diabetes MNT is more than mere calculation of a caloric prescription with

appropriate macronutrient composition and distribution of foods into meals and

snacks. It is a complex process that requires commitment on the part of clinicians

and the patient to design an individualized nutrition self-management plan. The

effectiveness of MNT is evaluated by success in achieving nutrition-related goals.

MNT cannot be limited to the time of diagnosis, but must continue through life

with adjustments made for growth and development; changes in lifestyle, diabetes

status, and health status; and advances in the field of diabetes nutritional care.

BIBLIOGRAPHY

American Diabetes Association: Nutrition recommendations and interventions

for diabetes (Position Statement). Diabetes Care 31:S61-S78, 2008

Dietary Supplement Health and Education Act of 1994, Public Law 103-417

(S.784) (1994) (codified at 42 USC 287C-11)

Elliott TD: Low glycaemic index, or low glycaemic load, diets for diabetes

mellitus (review): The Cochrane Collaboration, Published by John Wiley and

Sons, Ltd. 3:1-31, 2009 or Cochrane Database of Systematic Reviews 2009, Issue

1, Art. No.: CD006296, DOI: 10.1002/14651858,CD006296.pub 2

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Food and Nutrition Board Institute of Medicine: Dietary Reference Intakes for

Calcium, Phosphorus, Magnesium, Vitamin D and Fluoride. Washington, DC,

National Academy Press, 1999

Food and Nutrition Board Institute of Medicine: Dietary Reference Intakes

for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and

Amino Acids (Macronutrients). Washington, DC, National Academy Press,

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Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic

Acid, Biotin, and Choline. Washington, DC, National Academy Press, 1998

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Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Man-

ganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC,

National Academy Press, 2002

Foster-Powell K, Holt S, Brand-Miller, JC: International table of glycemic

index and glycemic load values. Am J Clin Nutr 76:5-56, 2002

Franz MJ, Bantle JP, Beebe CA, Brunzell JD, Chiasson JL, Garg A, Holzmeis-

ter LA, Hoogwerf B, Mayer-Davis E, Mooradian AD, Purnell JQ, Wheeler

M: Evidence-based nutrition principles and recommendations for the

treatment and prevention of diabetes and related complications (Technical

Review). Diabetes Care 25:148-198, 2002

Goebel-Fabbri AE: Disturbed eating behaviors and eating disorders in type 1

diabetes: clinical significance and treatment recommendations. Current Dia-

betes Reports 9:133-139, 2009

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ton, DC, National Academy Press, 1990

Jenkins DJA, Kendall CWC, Augustin LSA, Franceschi S, Hamidi M, Marchie

A, Jenkins AL, Axelsen M: Glycemic index: overview of implications in

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mittee on the Prevention, Detection, Evaluation, and Treatment of High Blood

Pressure. Washington, DC, National Institutes of Health National Heart

Lung and Blood Institute, 2004

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tenance become easier over time? Obesity Res 8:438-444, 2000

Mannucci E, Rotella F, Ricca V, Moretti S, Placidi GF, Rotella CM: Eating dis-

orders in patients with type 1 diabetes: a meta-analysis. J Endocrinol Invest 28

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Marsh K, Barclay A, Colagiuri S, Brand-Miller J: Glycemic index and glycemic

load of carbohydrates in the diabetes diet. Curr Diab Rep 11:120-127, 2011

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Miller WR, Rollnick S, (Eds): Motivational Interviewing: Preparing People for

Change, 2nd edition. New York, Guilford Press, 2002

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cal nutrition therapy in diabetes care? J Am Diet Assoc 103:827-831, 2003

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effectiveness of medical nutrition therapy in diabetes management. Diabetes

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Study. Diabetologia 40:1219-1226, 1997

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2005, accessed January 2008.

RESOURCES FOR PATIENT EDUCATION

Count Your Carbs: Getting Started. Alexandria, VA, American Diabetes Associa-

tion, and Chicago, American Dietetic Association, 2010

Choose Your Foods: Exchange Lists for Meal Planning. Alexandria, VA, American

Diabetes Association, and Chicago, American Dietetic Association, 2007

Choose Your Foods: Plan Your Meals. Alexandria, VA, American Diabetes Associa-

tion, and Chicago, American Dietetic Association, 2009

120 Medical Management of Type 1 Diabetes

Diabetes Care and Education Practice Group of the American Dietetic Association:

Ethnic and Regional Food Practices: A Series. Alexandria, VA, American Diabe-

tes Association, and Chicago, American Dietetic Association, various publi-

cation dates

Healthy Food Choices. Alexandria, VA, American Diabetes Association, and Chi-

cago, American Dietetic Association, 2009

Match Your Insulin to Your Carbs. Alexandria, VA, American Diabetes Association,

and Chicago, IL, Academy of Nutrition and Dietetics, 2011

McCarren M. Carb Counting Made Easy for People with Diabetes. Alexandria, VA,

American Diabetes Association, 2002

Warshaw HS: Diabetes Meal Planning Made Easy, 4th ed. Alexandria, VA, Ameri-

can Diabetes Association, 2010

Warshaw HS, Kulkarni K: Complete Guide to Carb Counting, 3rd ed. Alexandria,

VA, American Diabetes Association, 2011

Warshaw HS, Webb R: Diabetes Food and Nutrition Bible. Alexandria, VA, Amer-

ican Diabetes Association, 2001

RESOURCES FOR PROFESSIONALS

American Dietetic Association: Nutrition Practice Guidelines for Type 1 and Type 2

Diabetes Mellitus. Chicago, American Dietetic Association, 1998

Diabetes Care and Education Practice Group of the American Dietetic Asso-

ciation: The American Dietetic Association Guide to Diabetes Medical Nutrition

Therapy and Diabetes Education. Chicago, American Dietetic Association,

2003

Franz MJ, Evert A (Eds.): American Diabetes Association Guide to Medical Nutrition

Therapy for Diabetes. Alexandria, VA, American Diabetes Association, 2012

National Academies Press website for online review of publications on dietary

reference intakes for macronutrients and micronutrients: www.nap.edu

NIH Office of Dietary Supplements website (with IBIDS-International Biblio-

graphic Information on Dietary Supplements, which contains over 690,000

scientific citations and abstracts about dietary supplements): http://ods.

od.nih.gov/

Pastors J (Ed.): Diabetes Nutrition Q & A for Health Professionals: 101 Essential

Questions Answered by Experts. Alexandria, VA, American Diabetes Associa-

tion, 2003

Powers M (Ed.): Handbook of Diabetes Medical Nutrition Therapy. Gaithersburg,

MD, Aspen, 1996

122 Medical Management of Type 1 Diabetes

EXERCISE

n addition to insulin and medical nutrition therapy, physical activity and

exercise play a key role in diabetes management. Important health benefits of

physical activity for individuals with diabetes include a reduction in cardio-

vascular risk factors, increased sensitivity to insulin, better ability to maintain a

healthy weight and level of body fat, and a heightened sense of well-being. Given

these health benefits, regular physical activity should be considered an integral

part of the treatment plan for individuals with type 1 diabetes.

Because exercise can significantly affect blood glucose levels, it must be care-

fully integrated into the diabetes management regimen. When individuals with

type 1 diabetes are given appropriate guidance and support and attain good self-

management skills, they can achieve optimal glycemic control, exercise safely, and

achieve desired levels of exercise performance. Children and adolescents can partic-

ipate fully in gym classes, team sports, and other activities and have at least 60 min

of moderate to vigorous physical activity a day. In the absence of contraindications,

all adults should accumulate at least 30 min of moderate daily activity to improve

health and reduce risk of chronic disease. Adults with type 1 diabetes should be

encouraged to achieve at least this level of daily activity. Individuals with physical

limitations should be encouraged to maintain an active lifestyle and offered guid-

ance about safe and appropriate exercise options that will enable them to do so.

Success with any physical activity program is greatly enhanced when exercise

goals are appropriately established. Goals must be individualized based on a per-

son’s interests, likes and dislikes, unique lifestyle and psychosocial variables, age,

general health, level of physical fitness, and prior exercise experience.

GLYCEMIC RESPONSE TO EXERCISE

Exercise requires rapid mobilization and redistribution of metabolic fuels to

ensure an adequate energy supply for working muscles. For individuals who do

not have diabetes, this complex process is coordinated via neural and hormonal

responses that increase production of glucose and free fatty acids (FFAs) and facil-

itate uptake and utilization of these fuels by working muscle (Table 3.13). Insulin

levels fall while counterregulatory hormones rise, so that increased glucose utili-

zation by exercising muscle is matched precisely by increased glucose production

by the liver. For individuals with type 1 diabetes, the metabolic adjustments that

maintain fuel homeostasis during and after exercise are lacking. The result can be

a mismatch between hepatic glucose production and muscle glucose utilization

and significant deviation from normal glycemia. The glycemic response to exer-

cise can be variable and is influenced by multiple factors. These include

n overall metabolic control

n circulating insulin level

n plasma glucose at the start of exercise

n timing of exercise in relation to food intake

n glycogen stores

n level of training and fitness

n intensity, duration, time, and type of exercise

Tools of Therapy

123

Table 3.13 Metabolic Response to Light and Moderate Exercise:

Normal vs. Type 1 Ðiabetes

Normal Response

Response in Type 1 Diabetes

Insulin level decreases

Insulin level fails to change at the onset of

hglucose release from liver

exercise

hFFA mobilization

n insulin excess: muscle glucose uptake

n restricts use of glucose by nonexercising

exceeds liver glucose production

skeletal muscle

n insulin deficiency: liver glucose

production exceeds muscle uptake;

FFA release and ketone body formation

increase

n adequate insulin level: liver glucose out-

put matches muscle glucose uptake

Counterregulatory hormones increase

Counterregulatory hormones generally

hhepatic glucose production and

increase, although response may be

release

blunted in some individuals

hmuscle glycogenolysis

n adipose tissue lipolysis

Glucose uptake and utilization by working

muscle increases

muscle may or may not increase depend-

ing on insulin availability

Precise integration of glucose production

Potential mismatch between glucose pro-

and utilization and stable blood glucose

duction and utilization and variable blood

levels

glucose levels

Plasma insulin level is a primary determinant of the glycemic response to exer-

cise. In individuals who do not have diabetes, the circulating insulin level normally

falls at the onset of light or moderate-intensity exercise. In those with type 1 diabe-

tes, this response is absent, and insulin adjustments need to be made in anticipation

of exercise. If circulating insulin levels are too high, a state of relative hyperinsu-

linemia results, which leads to enhanced muscle glucose uptake, inhibited hepatic

glucose production, and potentiation of hypoglycemia. In contrast, if circulating

insulin levels are too low, as evidenced by pre-exercise hyperglycemia and poor met-

abolic control, an inadequate level of insulin combined with a heightened counter-

regulatory hormone release associated with exercise can lead to a marked increase

in glucose production and FFA mobilization from the liver. When availability of

these substrates exceeds muscle uptake, a further worsening of hyperglycemia and

ketosis may result.

POTENTIAL BENEFITS OF EXERCISE

Because individuals with type 1 diabetes are at high risk for the development

of cardiovascular disease, exercise, through its ability to improve multiple car-

diovascular risk factors, offers important health benefits. Regular exercise can

improve the lipoprotein profile by lowering VLDL cholesterol and triglycerides

124 Medical Management of Type 1 Diabetes

and by increasing HDL cholesterol. It also can reduce blood pressure, decrease

adiposity, improve cardiac work capacity, decrease platelet adhesiveness, and

lower the adrenergic response to stress.

Beyond cardiovascular benefits, participation in regular exercise assists with

weight loss and is essential for long-term success with maintaining a healthy

weight. It enhances sense of well-being and reduces feelings of stress and anxiety.

It improves muscle strength and agility, reduces bone loss, and prevents loss of

functional capacity that can occur with aging.

Although exercise increases insulin sensitivity and can lower the requirement

for insulin, it has not consistently been shown to lead to improvements in glyce-

mic control in individuals with type 1 diabetes as measured by A1C. However,

when exercising individuals learn to self-adjust their management to accommo-

date physical activity through careful meal planning, frequent SMBG and record

keeping, and correct application of insulin-adjustment strategies, they can achieve

excellent glycemic control and A1C levels.

POTENTIAL RISKS OF EXERCISE

Although exercise offers many health benefits, it also carries potential risks

for those with type 1 diabetes. Both acute complications, hyper- and hypogly-

cemia, and long-term microvascular and macrovascular complications may be

exacerbated by physical activity, especially if an exercise option is contrain-

dicated given existing complications or physical limitations or is incorrectly

performed.

Hyperglycemia and Hypoglycemia

Because exercise potentiates the effects of insulin, hypoglycemia may occur

during, immediately after, or many hours after a period of physical activity.

Hypoglycemia poses a risk to individuals who perform unusually long-duration

or strenuous exercise or to those who exercise sporadically without adjusting their

usual insulin dose or meal plan. In contrast, hyperglycemia can occur if pre-

exercise metabolic control is poor or if exercise is performed at a very high inten-

sity, anaerobic level (>80% of VO_2max).

Individual glycemic response patterns can differ markedly with exercise.

SMBG, use of continuous glucose sensing, careful record keeping, and rec-

ognition of glucose patterns with activity are important skills that can enable

individuals with type 1 diabetes to understand unique glycemic responses to

exercise, enhance their ability to make self-management decisions that sup-

port optimal glycemic control, and exercise safety and enhance performance.

Frequent SMBG helps with anticipation of the onset of hypo- or hyperglyce-

mia and enables individuals to make decisions about taking corrective actions

before either complication becomes severe. When data from monitoring are

carefully recorded and analyzed, they can provide a valuable basis for making

decisions about adjustments in management for subsequent exercise sessions.

In the future, it may be possible to use computer-based algorithms and sensor-

augmented pumps with threshold or predictive low glucose suspend features to

help avoid aberrations of glycemia during and after exercise.

Tools of Therapy

125

Macrovascular and Microvascular Complications

Although regular participation in physical activity tends to reduce cardio-

vascular risk factors, the risk of arrhythmias, myocardial ischemia or infarction,

and cardiac arrest is transiently elevated during exercise. Because individuals with

type 1 diabetes are at high risk for cardiovascular disease, careful evaluation to

assess risk for preexisting disease is advisable before an exercise program is initi-

ated, especially in previously sedentary adults with long duration of diabetes. For

those with known or suspected disease, a moderate, safe level of exercise that will

minimize risk of negative cardiac events should be prescribed.

Screening for microvascular diabetes complications before initiation of exer-

cise is also advisable. Worsening of complications is possible (Table 3.14) if

exercise is not carefully prescribed. As for the general population, exercise can

aggravate preexisting joint disease or lead to musculoskeletal injuries.

REDUCING EXERCISE RISKS

Potential exercise risks can be reduced if a thorough medical evaluation that

includes screenings for microvascular, macrovascular, and neurologic complica-

tions of diabetes precedes initiation of exercise (Table 3.15). Based on findings of

this exam, an individualized physical activity program should be carefully planned

and supported by an appropriate level of supervision to minimize exercise risks

and promote progressive gains in health and fitness. Exercise should be pre-

scribed with caution in individuals with previous poor metabolic control, includ-

ing severe hyperglycemia and ketonuria, frequent hypoglycemia or hypoglycemia

unawareness, cardiovascular disease, neuropathy, proliferative retinopathy, or

Table 3.14 Potential Risks of Exercise with Microvascular Diabetes

Complications

Microvascular Complication

Potential Exercise Risk

Proliferative retinopathy

Retinal detachment, vitreous or retinal

hemorrhage, blood pressure elevation

Peripheral neuropathy

Loss of protective sensation, soft tissue

injury, foot ulcers, injury to bones and

joints, infection

Autonomic neuropathy

Reduced heart rate and blood pres-

sure response to exercise, silent isch-

emia, orthostatic hypotension, impaired

counterregulatory response to exercise,

hypoglycemia unawareness, impaired

body temperature regulation, dehydration,

reduced exercise tolerance

Nephropathy

Marked blood pressure elevations with

high intensity, which may lead to transient

increases in proteinuria/albuminuria

126 Medical Management of Type 1 Diabetes

Table 3.15 Pre-exercise Testing Indications for Exercise Program

Greater Than Brisk Walking

n Age >40 years

c Nephropathy, including

n Age >35 years and

microalbuminuria

c Type 1 or type 2 diabetes of >10 years

n Any of the following, regardless of age:

duration

c Known or suspected coronary artery

c Hypertension

disease, cerebrovascular disease, and/

c Cigarette smoking

or peripheral vascular disease

c Dyslipidemia

c Autonomic neuropathy

c Proliferative or preproliferative

c Renal failure

retinopathy

nephropathy. Individuals with these complications should be offered guidance

about safe exercise options as well as activities that should be avoided (Table

3.16). Some individuals may benefit from initially participating in a supervised

exercise program. Performance of frequent SMBG before, during, and after exer-

cise should be encouraged.

Participation in a cardiac rehabilitation program may benefit individuals

with known cardiovascular disease. For these individuals, the exercise prescrip-

tion should be based on results of a graded exercise test. Special precautions and

monitoring are warranted for those who have hypertension or thyroid disease

Table 3.16 Exercise Options with Diabetes Complications

Diabetes

Inadvisable

Complication

Best Exercise Options

Exercise Options

Low-impact activities like

Pounding, jarring, or “head-

Proliferative

walking, swimming, low-

low” activities, high impact

retinopathy

impact aerobics, stationary

sports, heavy lifting, breath-

cycling

holding and Valsalva-like

maneuvers

Insensitive

Non-weight-bearing activities

Repetitive weight-bearing or

feet/periph-

like cycling, swimming, arm

high-impact activities like

eral vascular

chair exercises, light weight

prolonged walking or

insufficiency

lifting, yoga, tai chi

jogging

Nephropathy

Light to moderate daily activ

Heavy lifting or intensive

ities, low-intensity aerobic

exercise that results in blood

activity, light weight lifting

pressure increase

Hypertension

Dynamic exercises that

Heavy lifting and Valsalva-like

primarily use large, lower-

maneuvers

extremity muscle groups

Tools of Therapy

127

and for anyone who is taking cardiac or blood pressure medications that can mask

hypoglycemia, alter heart rate response to exercise, or influence cardiac work

capacity (e.g., b-blockers).

EXERCISE PRESCRIPTION

Before initiating exercise, all individuals should be given specific guidance

about appropriate exercise options, exercise goal-setting, methods for self-

monitoring exercise performance, strategies for maintaining optimal glycemic

control, and exercise safety precautions (Table 3.17).

The purpose of an exercise prescription is to offer specific exercise recom-

mendations that will safely and successfully guide an individual toward achieving

a level of physical activity that will improve health, fitness, functional capacity,

and quality of life. Individualization is the key to success of any exercise program.

Unique lifestyle variables, likes and dislikes regarding exercise options, stage of

readiness to make necessary lifestyle changes, age, prior exercise experience, and

level of fitness should all be considered.

Recommendations regarding frequency, intensity, duration, and type of

exercise should similarly be individualized. The most precise exercise prescrip-

tions are based on exercise testing that determines heart rate and blood pressure

response to exercise and aerobic capacity (VO_{2 max}).

An aerobic conditioning program is desirable for most individuals with dia-

betes. In addition, all people can benefit from informally increasing daily lifestyle

activities (e.g., walking and climbing stairs). The very unfit person may benefit

from beginning with a lifestyle activity program before progressing to structured,

aerobic exercise.

Whenever possible, an exercise contract that guides an individual toward

achieving exercise goals should be established. Goals should be established col-

laboratively with input from the exercising individual. The person’s progress

toward achieving goals should regularly be assessed and the exercise plan adjusted

as needed. Specific recommendations that are established with active involvement

and input from the individual with diabetes are most likely to lead to successful

exercise outcomes.

AEROBIC TRAINING

Individuals who are interested and physically able should be encouraged to

participate in aerobic activity. Aerobic training, which uses large muscle groups

repetitively and continuously for an extended time, promotes optimal improve-

ments in cardiorespiratory fitness, body composition, functional capacity, and

overall health when it is consistently done at a level that accrues an energy expen-

diture of 1,000-2,000 calories per week. Generally, aerobic activity should be

performed

n 20-60 min per session

n 150 min/week

128 Medical Management of Type 1 Diabetes

Table 3.17 Exercise Safety Guidelines

General

n Carry a medical identification card and wear an identification bracelet, necklace, or tag

that alerts others that individual has diabetes

n Exercise with an informed partner

n Measure pre-exercise blood glucose and take appropriate action:

u If <100 mg/dL: eat a carbohydrate-containing snack before exercising

u If >250 mg/dL: test for ketones and troubleshoot reason for hyperglycemia; if ketones

present, delay exercising until ketones are negative

n Frequently consume fluids before, during, and after exercise to prevent dehydration

n Do visual and tactile inspections of feet before and after exercise

n Wear footwear and clothing that is appropriate for the activity you plan to do and for the

exercise climate

n Avoid exercising in extreme heat, humidity, or cold

To Prevent Hypoglycemia

n Perform SMBG periodically during prolonged exercise; monitor more frequently

postexercise

n Be alert for signs of hypoglycemia during and several hours after an exercise session

n Avoid exercising during peak insulin action

n Administer insulin away from working limbs if exercise is to be initiated within 30 min of

an insulin injection

n Consider reducing the dose of insulin that will be acting during a period of exercise

n Have immediate access to a source of readily absorbable carbohydrate (such as glucose

tablets) to treat hypoglycemia

n at an intensity of 55-79% of maximum heart rate (40-74% of maximal

oxygen uptake reserve [VO₂R] or heart rate reserve [HRR]), or rating of

perceived exertion (RPE) of 12-13-14 “somewhat hard” level of effort; a

lower intensity of 55-65% of maximum heart rate (40-50% of VO₂R or

HRR), and RPE of 12 is appropriate for those who are unfit (Table 3.18)

Participation in aerobic exercise is safest and most effective if individuals

monitor exercise intensity to ensure that they are working in an appropriate

“target zone” or level of effort. Three methods that can be used to monitor

exercise intensity are heart rate or pulse count monitoring, RPE, and the “talk

test” (Table 3.18). Individuals with known coronary artery disease should be

informed about symptoms of myocardial ischemia. Exercise-related chest pain

or discomfort, excessive shortness of breath, lightheadedness, or nausea are all

indicators that an individual should immediately stop an activity. Any discom-

fort or worrisome symptoms associated with exercise should be reported to an

individual’s physician.

Each session of aerobic exercise should include a 5- to 10-min warm-up and a

5- to 10-min cool-down period. The warm-up should include light general mus-

cle movement, e.g., slow walking or stationary cycling, followed by stretching.

Tools of Therapy

129

Table 3.18 Methods of Determining and Monitoring Exercise

Intensity with Exercise

Target Heart Rate

Rating of Perceived Exertion

“Talk Test”

Monitor

Determine perception of effort

Assess ability to talk or carry

10-s pulse count

required or level of difficulty

on a conversation while exer-

by palpating

associated with exercising at a

cising as an indicator of staying

carotid or radial

given workload

within/not exceeding an aero-

pulse or use heart

bic training level

rate monitor

Target heart rate:

Target: rating of perceived

Target: Maintaining ability to

55-79% of HR_max

exertion of 12-13-14 “some-

talk during an exercise ses-

or 40-74% VO₂R

what hard” level of effort

sion; avoid extreme shortness

or HRR*

of breath

*HR_max = 220 - age (or maximal heart rate achieved on exercise stress test)

VO₂R = VO_2max - resting VO₂ (maximal oxygen uptake reserve; can be calculated if VO_2max is measured

during exercise stress test). HRR = (HR_max - HR_rest) + HR_rest (heart rate reserve; formula accounts for true

resting as well as maximal heart rate)

The warm-up should be followed by the more vigorous aerobic training period

during which the exercise “target zone” should be achieved. At the end of an

exercise session, a cool-down period should include light general muscle move-

ment and stretching. Calisthenics or other light resistance activities can be

incorporated into the cool down. The heart rate should approach a resting level

(<100 beats/min) before the cool down is completed.

When prescribing exercise, it is important to start each individual at a level

that can reasonably be achieved. This may require that an individual who is

very deconditioned begin by doing short, 5- to 10-min exercise sessions two to

three times per day. The duration of each session can gradually be increased as

a person becomes more fit. As the duration of each exercise session increases,

the number of daily sessions can be reduced. It is important not to overlook the

considerable health benefits that can be gained even if exercise is performed

at an intensity below an optimal target range for improving cardiorespiratory

fitness. Promoting all types of physical activity, even forms that require a low-

to-moderate level of effort, is important. For individuals who dislike vigorous

exercise, a physical activity program that focuses on weekly energy expenditure

rather than on intensity of exercise may support improved adherence and better

exercise outcomes.

Resistance exercises such as weight lifting or calisthenics can improve body

composition, increase muscle strength and endurance, improve flexibility, increase

insulin sensitivity and glucose tolerance, and decrease cardiovascular risk factors.

Individuals who are interested in resistance exercise should be carefully screened

for diabetes complications, especially proliferative retinopathy, so that a program

can be safely adapted to minimize risk of aggravating existing complications. All

individuals should be taught proper technique at the onset of a training program

to minimize the risk of injury.

130 Medical Management of Type 1 Diabetes

If a diabetes clinician does not feel knowledgeable enough about principles

of exercise to prescribe and supervise an aerobic exercise program, a referral

should be made. Hospital-based cardiac rehabilitation or wellness programs,

YMCA programs, and programs offered through college and university physi-

cal education departments can be excellent and appropriate options for exercise

referral. A well-qualified exercise physiologist or exercise specialist who has

clinical experience and is knowledgeable about diabetes can also be a valuable

resource.

STRATEGIES FOR MAINTAINING OPTIMAL

GLYCEMIC CONTROL WITH EXERCISE

Based on results of SMBG, CGM, record keeping, uploads, and identifica-

tion of exercise-related blood glucose patterns, individuals with type 1 diabetes

can learn to make adjustments in their diabetes management to maintain optimal

glycemic control with exercise. Adjustments can be made in the meal plan, insu-

lin dosage, or both in combination. Diligence with glucose monitoring either by

SMBG or CGM (before, during, and after exercise), careful record-keeping, and

uploading data to retrospectively determine glucose response patterns are crucial

for success with making sound exercise-related adjustment decisions.

Adjusting Carbohydrate Intake

The decision to adjust carbohydrate intake for exercise should be based on

a number of factors. These include pre-exercise blood glucose level, planned

exercise intensity and duration, the time of day of the planned activity and time

in relation to previous food intake, an individual’s level of training, and previ-

ous glycemic response to exercise. Additional carbohydrate may be necessary to

prevent hypoglycemia, treat hypoglycemia if it occurs, or fuel muscle and delay

fatigue during periods of prolonged activity.

When an activity session is of short duration or is unplanned, consuming

additional carbohydrate is useful. For moderate activity lasting <30 min, insulin

adjustment is rarely necessary, but a small snack that provides ~15 g carbohydrate

may be needed. Consuming additional carbohydrate is certainly indicated if the

pre-exercise blood glucose is <100 mg/dL (<5.6 mmol/L). During periods of pro-

longed or intense exercise when energy expenditure is high, additional carbohy-

drate is often necessary. Intake of 15 g carbohydrate every 30-60 min of activity

is a general, safe starting guideline. Extra carbohydrate may also be needed in

the postexercise period when insulin sensitivity is increased and glycogen stor-

age is enhanced. Intake of additional carbohydrate at this time can reduce risk of

hypoglycemia and enhance glycogen storage. For individuals who exercise in the

late afternoon or evening, it is particularly important to be alert to the possibility

of nocturnal hypoglycemia and adjust the evening snack as needed to prevent its

occurrence.

The rigid recommendation to consume extra carbohydrate based only on the

planned intensity and duration of exercise and without regard to the glycemic

level at the start of exercise, previous metabolic response to exercise, and insu-

lin therapy is no longer appropriate. Such an approach can easily neutralize the

Tools of Therapy

131

beneficial blood glucose-lowering effect and energy deficit that results from exer-

cise. The amount of carbohydrate required to prevent hypoglycemia and opti-

mize exercise performance must be determined on an individual basis and can

vary with each exercise situation.

Adjusting Insulin

The increasing use of intensive insulin therapy has provided individuals with

type 1 diabetes with great flexibility and the ability to make precise insulin adjust-

ments for various activities. In certain exercise situations, it may be necessary to

reduce the insulin dosage to prevent hypoglycemia.

A reduction in the insulin dosage often is necessary when a vigorous exercise

session lasts greater than or equal to 30 min. The specific adjustment that will

be needed depends on the insulin dosage, the timing of exercise in relation to

insulin “peak” action time, and the planned intensity and duration of an activity.

For a moderate amount of exercise, a modest reduction (~20-30%) in the insulin

component that is most active during the period of exercise may be sufficient to

prevent hypoglycemia. However, for very prolonged, vigorous exercise such as

distance running, cross-country skiing, cycling, or backpacking, a large decrease

in the total daily insulin dosage (by as much as 50-80%) may be needed to pre-

vent hypoglycemia. In this case, both short- or rapid- and longer-acting insulin

may need to be decreased proportionally. The DirectNet study in children using

CSII showed that during strenuous activity in children, basal insulin delivery via

the insulin pump should be discontinued to avoid hypoglycemia. Care should

be taken to avoid discontinuation of insulin delivery for long periods of time. In

addition, DirecNet has shown that after 1 h of exercise in the afternoon, children

experience significantly more hypoglycemia during the ensuing night compared

to sedentary days. The nadir glucose was between midnight and 2 a.m. after an

afternoon exercise session between 4 and 6 p.m. In adults, or with less strenuous

activity, lowering pump basal rates rather than suspending delivery may be as

effective and safer. Insulin reductions may also be necessary during the postexer-

cise recovery period.

An elevation in the pre-exercise blood glucose level can be an indicator of an

insulin-deficient state. Supplemental insulin may be necessary to correct a low

insulin level and improve metabolic control before exercise is initiated.

If an exercise session is to be initiated within 30 min of an insulin injection,

the injection should be administered in an area of the body that will not pre-

dominantly be used for the activity. Insulin absorption and peak action time can

be accelerated if insulin is injected into an area of working muscle shortly before

initiation of exercise. The abdomen is generally the site of choice.

CONCLUSION

Long recognized as a cornerstone of diabetes management, exercise is an all

too often underutilized therapeutic modality. Although exercise carries potential

risks for people with diabetes, with careful planning, it can provide numerous

health benefits that far outweigh these risks. Using established, sound guidelines,

132 Medical Management of Type 1 Diabetes

physicians and diabetes educators can frame safe and effective exercise programs

that will enhance the health and well-being of individuals with type 1 diabetes.

BIBLIOGRAPHY

American College of Sports Medicine: The recommended quantity and quality

of exercise for developing and maintaining cardiorespiratory and muscular

fitness and flexibility in healthy adults (Position Stand). Med Sci Sports Exerc

30:975-991, 1998

American Diabetes Association: Handbook of Exercise in Diabetes. Ruderman

N, Devlin JT, Schneider SH, Kriska A, Eds. Alexandria, VA, American

Ðiabetes Association, 2002

American Diabetes Association: Physical activity/exercise and diabetes (Position

Statement). Diabetes Care 27 (Suppl. 1):S58-S62, 2004

Centers for Disease Control and Prevention and the American College of

Sports Medicine: Physical activity and public health: a recommendation.

JAMA 273:402-407, 1995

Colberg S: The Diabetic Athlete. Champaign, IL, Human Kinetics, 2001

Chu L, Hamilton J, Riddell MC: Clinical management of the physically active

patient with type 1 diabetes. Phys Sportsmed 39:64-77, 2011

Lehmann R, Kaplan V, Bingisser R, Bloch KE, Spinas GA: Impact of physical

activity on cardiovascular risk factors in IDDM. Diabetes Care 20:1603-

1611, 1997

Taplin CE, Cobry E, Messer L, McFann K, Chase P, Fiallo-Scharer R: Prevent-

ing post-exercise nocturnal hypoglycemia in children with type 1 diabetes.

J Pediatr 157:784-788, 2010

Tsalikian E, Mauras N, Beck RW, Tamborlane WV, Janz KF, Chase HP,

Wysocki T, Weinzimer SA, Buckingham BA, Kollman C, Xing D, Ruedy

KJ, the Diabetes Research in Children Network Direcnet Study Group:

Impact of exercise on overnight glycemic control in children with type 1

diabetes mellitus. J Pediatr 147:528-534, 2005

US Department of Health and Human Services: Physical Activity and Health: A

Report of the Surgeon General. Centers for Disease Control and Prevention,

National Center for Chronic Disease Prevention and Health Promotion,

Washington, DC, US Govt. Printing Office, 1996

Highlights

Special Situations

DIABETIC KETOACIDOSIS

n Frequent reexamination of labo-

ratory indices is imperative, at mini-

n Diabetic ketoacidosis (DKA)

mum, every hour during the first 4 h

is a life-threatening but reversible

and at least every 4 h thereafter.

complication characterized by severe

disturbances in carbohydrate, fat, and

n Insulin therapy and hydration will

protein metabolism.

reverse acidosis, and routine bicar-

bonate administration is not recom-

n DKA is always due to insulin defi-

mended. Potassium administration

ciency, either absolute (e.g., a previ-

is recommended for all patients once

ously undiagnosed patient or omitted

urine output and renal function are

insulin) or relative (e.g., too little

assessed.

insulin injected or antagonism by

stress [counterregulatory] hormones).

n The cause of DKA must be

aggressively pursued. Potential com-

n Any major stress may precipitate

plications of therapy and how to avoid

DKA in a patient with diabetes who

them are outlined.

lacks sufficient circulating insulin.

n DKA often can be prevented,

n The clinical signs and symptoms

given appropriate patient education

of DKA are listed in Table 4.1. They

and prompt physician attention.

usually include polyuria, polydipsia,

hyperventilation, dehydration, the

fruity odor of ketones, and distur-

HYPOGLYCEMIA

bances in the conscious state from

drowsiness to frank coma.

n Hypoglycemia is a common side

effect of insulin therapy. Mild hypo-

n The initial goal of therapy should

glycemic reactions usually consist of

be to correct life-threatening abnor-

autonomic (neurogenic or adrenergic)

malities, i.e.,

symptoms, e.g., tremors, palpitations,

sweating, and excessive hunger. Mod-

• dehydration

erate and severe reactions include

• hyperglycemia

autonomic as well as neuroglycopenic

• acidosis

symptoms, e.g., difficulty thinking,

confusion, headache, slurred speech,

• potassium deficiency

dizziness, seizures, or coma.

135

n Mild hypoglycemic reactions may

PREGNANCY

produce only minimal disruption of

daily activities. Moderate and severe

n Women with type 1 diabetes who

insulin reactions may severely harm

plan their pregnancies and receive

health and morale and should be

optimal care by an experienced dia-

avoided.

betes management team can expect a

pregnancy outcome similar to that of

n Certain circumstances favor

women who do not have diabetes.

development of prolonged,

incapacitating, and occasionally

n Excellent glycemic control during

life-threatening hypoglycemia, i.e.,

pregnancy has been shown to bring

unequivocally beneficial results to

• hypoglycemia unawareness

both mother and fetus.

• antecedent hypoglycemia

• failure to notice symptoms because

n Poor perinatal outcome is asso-

patient is sleeping or attention is

ciated with poor glycemic control,

elsewhere

ketonemia, and vasculopathy.

• intensive glycemic control

n Patients should be as near to nor-

• long duration of diabetes

moglycemia as possible at the time

• certain medications or drugs,

of conception and throughout the

including alcohol

1st trimester to decrease incidence

of congenital malformations, and

n The factors precipitating an epi-

throughout the remainder of the

sode of hypoglycemia can often be

pregnancy to reduce the risk of mac-

identified, allowing prevention of

rosomia.

future reactions in similar circum-

stances.

n Frequent SMBG is mandatory

during pregnancy. Insulin pump

n Self-monitoring of blood glucose

therapy and continuous glucose mon-

(SMBG) should be used to full advan-

itoring may aid in achieving optimal

tage for detection and treatment of

glycemic control during pregnancy.

hypoglycemia. Those with frequent or

severe episodes might consider con-

n Most women with type 1 diabe-

tinuous glucose monitoring. Changes

tes may be managed as outpatients

in insulin injection, eating, or exercise

throughout gestation.

schedules and travel call for increased

frequency of monitoring.

n Tests to assess fetal growth and

well-being should be conducted at

n Guidelines for treatment of mild,

appropriate times. Timing of deliv-

moderate, and severe reactions should

ery, management during labor and

be clearly understood by patient, fam-

delivery, and postpartum care are

ily, and school and business associates.

covered. Family planning and con-

traception must be reviewed with the

n Hypoglycemia may occasionally

patient during the postpartum period.

lead to rebound hyperglycemia and

should be recognized and appropri-

ately treated if it occurs.

136

SURGERY

n In patients with DKA who need

emergency surgery, efforts should be

n Given appropriate preparation

made to delay surgery until DKA is

and management, patients with type

treated.

1 diabetes are subject to little more

than normal risk during surgery.

n Guidelines are given for

•

major elective surgery

n Whenever possible, the patient

• major emergency surgery

should be in the best possible general

health and glycemic control before a

• surgery with local anesthesia

surgical procedure.

ISLET TRANSPLANTATION

n The objectives of glycemic man-

agement before, during, and after an

n Significant progress has been

operation are to prevent hypoglyce-

made in human islet allotransplanta-

mia and excessive hyperglycemia and

tion, but limitations remain and the

ketoacidosis.

procedure remains experimental.

In a long-term clinical trial, 44% of

n Because hypoglycemia is particu-

patients achieved insulin and nor-

larly dangerous in the unconscious

malization of A1C at 1 year post-islet

patient, plasma glucose should gener-

transplantation, although a signifi-

ally be kept between ~100 and 150

cant proportion of patients required

mg/dL (~5.6 and 8.3 mmol/L) during

resumption of insulin therapy in

and after the operation.

subsequent years of follow-up. The

procedure also carries risks of hepatic

n Intravenous insulin delivery

bleeding after the administration

is preferred during surgery,

of islets into the portal vein and

although subcutaneous insulin

complications of long-term immu-

may be used if the patient has stable

nosuppression. Research is ongoing

glucose control, the procedure is

to improve these results, minimize

relatively minor and of short dura-

the risks from immunotherapy and

tion, and recovery is expected to be

develop other potential sources of

rapid.

islet cells.

137

Special Situations

DIABETIC KETOACIDOSIS

iabetic ketoacidosis (DKA) is a life-threatening but reversible complica-

tion characterized by severe disturbances in protein, fat, and carbohy-

drate metabolism that result from insulin deficiency. DKA is a medical

emergency requiring treatment in a medical intensive care unit or equivalent

setting.

In DKA, the arterial pH is <7.3, plasma bicarbonate is <15 mEq/L, blood glu-

cose is generally >250 mg/dL (>13.9 mmol/L), and blood ketones are elevated. In

mild DKA, the bicarbonate level is 15-18 mEq/L. DKA is always due to absolute

or relative insulin deficiency. The counterregulatory or stress hormones include

glucagon, catecholamines, cortisol, and growth hormone and are markedly ele-

vated in DKA. Acting in concert with the deficiency of insulin, they augment the

metabolic derangements characteristic of DKA:

n hyperglycemia secondary to increased glucose production and decreased

utilization

n osmotic diuresis and dehydration secondary to hyperglycemia

n hyperlipidemia secondary to increased lipolysis

n acidosis secondary to increased production and decreased utilization of

acetoacetic acid and 3-b-hydroxybutyric acid derived from fatty acids

n an increased anion gap secondary to elevated ketoacids and lactate

PRESENTATION OF DKA

The clinical diagnosis of DKA is usually apparent in a patient known to have

diabetes. However, DKA may not be readily considered in new-onset diabetes,

particularly in very young children, in whom a delay in diagnosis may result in

life-threatening complications. Those at higher risk are children <5 years and/or

who, due to social or economic hardships, do not have access to regular medical

care. A blood glucose concentration <250 mg/dL (<13.9 mmol/L) usually excludes

DKA unless the patient has been partially treated with insulin and fluids before

presentation and has severely restricted his or her calorie intake.

For patients who already have diabetes, the chances of developing DKA are

1-10% each year; however, unbalanced familial relationships, poor metabolic

control, psychiatric diagnosis, eating disorders, limited medical care, and insulin

pump use can cause patients to be at a higher risk of DKA development.

139

140 Medical Management of Type 1 Diabetes

Table 4.1 Common Presenting Symptoms and Signs in DKA

Symptoms

Signs

Nausea and vomiting

Dehydration

Thirst and polyuria

Hyperpnea or Kussmaul breathing

Abdominal pain

Impaired consciousness and/or coma

Somnolence

Fruity odor

Clinical Signs and Symptoms

The clinical signs and symptoms of DKA include polyuria, polydipsia, hyper-

ventilation, and dehydration (Table 4.1). The fruity odor of ketones may be appar-

ent, especially on the breath, and disturbances in consciousness may vary from

drowsiness to frank coma. Abdominal pain in association with an elevated white

blood cell count and serum amylase may occur but resolves with therapy. If severe

abdominal pain persists, a surgical consultation should be obtained, because an

acute condition such as appendicitis, bowel perforation, pancreatitis, or infarction

may coexist and may have been the DKA precipitant.

Precipitating Factors

Any major stress may precipitate DKA in a patient with diabetes. Infections

such as pneumonia, meningitis, gastroenteritis, and influenza are some of the many

heterogeneous causes, as are trauma or myocardial infarction. In most patients, it

is possible to identify a specific precipitating cause. Among the most common are

deliberate or inadvertent omission of insulin. The latter is particularly common

following interruption of insulin pump delivery because of the limited available

depot insulin when only rapid-acting insulin is being used. Another common cause

of DKA is secondary to mismanagement of sick days, i.e., withholding insulin

from a patient who is vomiting and unable to eat and mistakenly believes this

situation may result in hypoglycemia (Table 4.2).

Table 4.2 Points to Consider in Treating DKA

n A precipitating cause can be identified in

n Administration of glucose is necessary to

most patients.

clear ketosis.

n An ECG is indicated in all adult

n Bicarbonate is rarely needed.

patients.

n Cautious replacement of phosphate is

n Isotonic saline is initially preferred to

sometimes used.

rehydrate patients.

n Preventing DKA is a long-term goal of

n Intravenous insulin is the preferred route

sound diabetes management.

of delivery.

n DKA patients are deplete in total-body

potassium.

Special Situations

141

ACUTE PATIENT CARE

The initial goal of therapy should be to correct life-threatening abnormali-

ties, i.e., dehydration, insulin deficiency, and potassium deficiency. Fully cor-

recting all biochemical abnormalities will take several days. During the first 12 h

of therapy, the condition must be reevaluated frequently. Particular attention

should be paid to the plasma potassium concentration as well as frequent assess-

ment of neurologic changes (headache, mood shifts) or other symptoms of cere-

bral edema. A flow sheet tabulating successive changes in the patient’s condition

must be maintained for all patients (Table 4.3). The degree of hyperglycemia,

acidosis, dehydration, and conscious state is variable. If the patient’s clinical con-

dition deteriorates after initial therapy has begun, help from an appropriate spe-

cialist is needed.

Therapy, laboratory data, and clinical assessment should be monitored at

frequent intervals for the first 12-24 h. Patients are generally best followed in

an intensive care setting. For a treatment schedule, see Tables 4.4 and 4.5.

Rehydration Process

Significant dehydration is present in all patients with DKA. There are many

routes of water and/or electrolyte loss, including 1) polyuria, 2) hyperventila-

tion, and 3) vomiting and diarrhea. The best index of the degree of dehydration

Table 4.3 Ketoacidosis Flow Sheet

Monitoring Interval

Clinical

Mental status

1 h

Vital signs (T, P, R, BP)

1 h

ECG

Initially and as indicated

Weight

Initially and daily

Therapy

Fluid intake and output (ml/h)

4 h

Insulin (units/h)

1 h

Potassium (mEq/h)

4 h

Glucose (g/h)

4 h

Bicarbonate and phosphate (if indicated) (mEq/h)

4 h

Laboratory

Glucose (bedside)

1 h

Potassium, pH

2 h

Sodium, chloride, bicarbonate

4 h

Phosphate, magnesium

4 h

BUN and creatinine

4 h

142 Medical Management of Type 1 Diabetes

is the magnitude of acute weight loss, which may be determined if the patient’s

baseline weight is known. Other clinical indices include orthostatic hypotension,

dry mucous membranes, prolonged capillary refill, decreased tissue turgor, and

thirst. A decrease in urine output is less reliable because of persistent osmotic

diuresis with hyperglycemia. It is reasonable to assume with DKA an average

water loss of 5-10% of total body weight.

Adequate rehydration is extremely important in initial therapy. Isotonic saline

(0.9% normal saline [NS]) is usually the initial choice of rehydrating fluid (Table

4.4) at a rate of 10-20 mL/kg/h in the absence of shock. A patient in shock should

be given isotonic saline or Ringer’s lactate (crystalloid, not colloid) at a rate

of 20 mL/kg/h to restore circulation. If circulation is not re-established, repeat

boluses of 10 mL/kg/h can be given over 1-2 h, but likely 30-40 mL/kg total will

be the maximum required. For patients who are hypertensive, hypernatremic, or

at risk for congestive heart failure, a solution containing 0.45% isotonic saline

may be preferable. In young children (age <10 years), calculate fluid replacement

according to body surface area, not weight (e.g., a 30-kg child has ~1 m² body

surface area).

Because calculations of dehydration are often over- or underestimated, IV

and oral hydration should not exceed a rate of 1.5-2 times the required fluid

intake for normal hydration for the age/weight/body surface of the patient.

Insulin Replacement

Because the cause of DKA in all patients includes absolute or relative insulin

deficiency, insulin must be provided. Insulin is required for suppression of ketone

body production and is thus necessary to correct acidosis. Insulin also inhibits

glycogenolysis and gluconeogenesis, suppresses lipolysis, and facilitates the con-

servation of sodium and other electrolytes by the kidney.

Table 4.4 Fluid Replacement

Hour 1-2

Provide 10-15 ml/kg isotonic saline (0.9% normal saline [NS]) or 500 ml/m²/h; if patient

has heart disease, administer fluid cautiously, e.g., according to central venous pressure.

Hour 3-4

Reduce fluid rate to 7.5 ml/kg/h in adults or 2,500 ml/m²/24 h in children.

Adjust fluid rate to meet clinical need. Do not consider rate of urine output in fluid replace-

ment calculation, except in rare occasions. Fluid replacement should be administered

evenly over 48 h after initial resuscitation.

When blood glucose reaches 250 mg/dL (<13.9 mmol/L), change fluid to 5% dextrose in

0.45% NS at 150-250 ml/h.

Continue intravenous fluids, including insulin, until acidosis is corrected. Then change to

short- or rapid-acting insulin subcutaneously every 4 h, giving the first dose 2 h before dis-

continuing intravenous insulin.

144 Medical Management of Type 1 Diabetes

Short-acting (regular) or rapid-acting insulin should be used initially at a

rate of 0.1 units/kg/h (or 0.05 units/kg/h for more sensitive patients). Replac-

ing insulin with a continuous intravenous infusion is the most direct route and

is preferred if methods are available to regulate the infusion rate. Insulin infu-

sion should be initiated 1-2 h post fluid replacement/initial volume expansion.

Replacement via the intramuscular route is an alternative, but only if unable to

give IV insulin and should not be used in patients with impaired peripheral cir-

culation. This titration method will adapt to any degree of insulin resistance and

prevent severe hypoglycemia as insulin resistance wanes.

Insulin infusion must be continued until both hyperglycemia and acidosis

are corrected. Treating acidosis requires higher doses of insulin than reversing

hyperglycemia, and it will take longer to regulate than hyperglycemia alone.

Therefore, when blood glucose levels approach <250 mg/dL (13.9 mmol/L),

5% glucose should be added to the rehydrating fluid to allow continuation of

adequate doses of insulin therapy until acidosis resolves. Not giving glucose will

delay clearing acidosis. Some clinicians, particularly those treating patients in

the pediatric age range, recommend moderating the glycemic target to ~200-mg/dL

(~11.1-mmol/L) range for 12 h, fearing that more rapid reduction in blood glu-

cose increases the risk of cerebral edema.

Particular attention should be paid to the decrease rate of serum glucose at

initial rehydration, as glucose levels will drop with fluid intake. After this initial

drop, and with the administration of insulin, the rate of decrease is approximately

35-90 mg/dL per hour. The addition of 5% glucose to the saline solution can be

added before the serum glucose reaches 250 mg/dL if the rate of fall is more rapid.

Potassium Replacement

Patients with DKA are depleted in total body potassium, despite a normal

or even elevated serum potassium level. The reasons for this are complex and

include the catabolic state, potassium wasting in urine secondary to polyuria,

inability of kidney to rapidly conserve potassium, and often, the effects of vomit-

ing and/or diarrhea.

Correct potassium replacement requires both caution and timely action. The

following procedure is recommended:

n Establish urine output to be certain patient does not have renal failure.

n Send blood samples to the laboratory to measure serum potassium.

n Do an electrocardiogram (ECG) to rapidly estimate whether hypokalemia

or hyperkalemia is present (high peaked T-waves in hyperkalemia; low

T-waves with U-waves in hypokalemia). Patients who are hypokalemic

should receive potassium at initial rehydration. Patients who are hyperka-

lemic should not receive potassium until after initial expansion and with

insulin initiation.

n Begin potassium replacement at the suggested rate (Figure 4.1).

n When laboratory reports are available, alter rate with the goal of

maintaining the plasma potassium level between 3.5 and 6.0 mEq/L at

all times.

Special Situations

145

If starting potassium at initial volume expansion, a concentration of 20 mEq/L

should be used. If starting at insulin initiation, a concentration of 40 mEql/L is

advised and should continue through the entirety of therapy. Potassium can be

a combination of potassium phosphate or potassium chloride or acetate. When

combining, use a concentration of 20 mEql/L of each acetate and phosphate. IV

administration should not exceed 0.5 mEq/kg/h, and if no response in levels is

apparent and hypokalemia persists, reduction in insulin administration can occur

until potassium levels begin to rise.

Once insulin infusion is begun, potassium replacement is particularly critical.

Insulin tends to lower serum potassium by enhancing its movement back into

cells, and hypokalemia-induced cardiac arrhythmia may result from insufficient

replacement. If there is anuria, potassium should be infused with special caution

and stringent monitoring.

Bicarbonate and Phosphate Replacement

Although it seems reasonable to administer sodium bicarbonate to the patient

with DKA to correct the metabolic acidosis with alkali, it is not clear whether the

potential benefits outweigh potential risks. The potential harmful effects are accel-

erated reduction in plasma potassium concentration and exacerbated intracellular

acidosis. Randomized trials have shown no better outcomes in patients with DKA

with bicarbonate therapy. For these reasons, routine bicarbonate administration is

not recommended in most cases of DKA when pH is greater than or equal to 7.1.

With severe acidosis (i.e., arterial pH <7.0), particularly when hypotension, shock,

and arrhythmias are also present, or a patient has life-threatening hyperkalemia,

bicarbonate should be given as an infusion of 1-2 mEq/kg over 60 min and then

after checking plasma bicarbonate level. Repeat as needed until pH is >7.1.

Patients presenting in DKA are usually phosphate depleted and as with potas-

sium, insulin administration enhances the movement of phosphate into cells. This

can further reduce the plasma phosphate concentration.

There are pros and cons to administering phosphate, an ion important to

many chemical reactions at the cellular level. One potential benefit is that hyper-

chloremia may be less likely to result when potassium is replaced as potassium

phosphate instead of potassium chloride. However, administering too much

phosphate can induce hypocalcemia. Therefore, calcium levels should be checked

before phosphate is administered.

Although routine phosphate replacement has not been shown to be of ben-

efit in the treatment of DKA, conservative potassium phosphate administration

not to exceed 1.5 mEq/kg/24 h may be recommended, especially in patients with

severe hypophosphatemia. The bulk of the potassium is administered as potas-

sium chloride.

OTHER IMPORTANT CONSIDERATIONS

It is important to pursue other aspects of therapy while correcting the labora-

tory abnormalities. The cause of DKA must be pursued aggressively. The phy-

sician must be certain that there is no coexisting medical condition. In several

reported series of adult patients admitted to the hospital with DKA, infection was

146 Medical Management of Type 1 Diabetes

the most common precipitating factor. Therefore, depending on clinical signs

and symptoms, a chest X-ray and cultures of the urine, throat, sputum, or blood

may be warranted.

An ECG is mandatory in adults to access potassium levels and also because

myocardial infarction may precipitate DKA. The clinician should also carefully

investigate all possible causes of abdominal pain.

Malfunction of the infusion system is the most likely cause of DKA in those

on pumps and the most readily treatable cause of DKA. Recommendations for

prevention and treatment of impending DKA in patients on pump therapy are

covered more fully in Chapter 3.

In addition to determination of the cause of DKA, other supportive therapy

must be considered. Ensuring an airway and inserting a nasogastric tube to drain

gastric contents in comatose patients are strongly recommended to prevent aspi-

ration pneumonia. Low-dose subcutaneous heparin (5,000 units every 12 h) is

often recommended to prevent hypercoagulability, especially in elderly patients.

However, data that demonstrate the benefit of heparin administration in DKA

are lacking.

Be alert to complications of treatment. Potential complications directly

attributable to the treatment of DKA must be anticipated.

n Generally, glucose will be normalized more quickly than acidosis. Pre

mature discontinuation of insulin may result in persistence and worsening

of ketoacidosis. Hyperchloremic acidosis can also occur as the result of

excessive chloride replacement as both sodium and potassium chloride.

n Failure to give IV glucose at 5-6.25 g/h when blood glucose is <250 mg/dL

(<13.9 mmol/L) will cause persistence of ketogenesis due to inability to

continue high-dose insulin.

n Hypoglycemia can occur if the insulin infusion rate is not lowered after

correction of acidosis, as insulin resistance improves and glucose toxicity

clears.

n Nausea and vomiting from gastric atony due to hypokalemia or from

feeding the patient before gastric peristalsis has returned can result in

aspiration pneumonia.

n Hypokalemia from inadequate or delayed potassium replacement.

Cerebral Edema

Cerebral edema is the leading cause of death from DKA in children and youth;

the incidence of cerebral edema is 0.5-0.9% and, once developed, the mortality

rate is 21-24% with an almost equal percent suffering permanent neurologic

impairment and 60-90% of DKA deaths are from cerebral edema compared to

those with neurologic recovery. Those who have severe DKA appear to be at

heightened risk to develop cerebral edema. Characteristics include young age,

new-onset diabetes, and long duration of symptoms. Retrospective studies have

shown that risk factors for cerebral edema include excess fluid administration,

insulin administration in the first hour of treatment, a greater degree of hypocap-

nia, increased serum urea nitrogen, use of bicarbonate, and an attenuated rise in

Special Situations

147

measured serum sodium concentrations during treatment. The pathophysiology

for cerebral edema, previously thought secondary to intracerebral osmotic shifts,

may be, in fact, due to cerebral ischemia and reperfusion injury. It remains critical

to determine the mechanism of cerebral edema, since this may alter the approach

to the initial treatment of DKA and rehydration strategy.

Clinically significant cerebral edema usually develops 4-12 h into ther-

apy, though it can occur before, as well, and can be detected by a changing

neurologic examination that may include onset of severe headache, pupillary

changes, incontinence, vomiting, hypertension and bradycardia, neurogenic

respiratory pattern, and decorticate or decerebrate posturing. Once diag-

nosed, cerebral edema is treated by the administration of mannitol 0.5-1 g/kg

IV over 20 min. This is repeated if there is no initial response in 30 min to

2 h. Hypertonic saline (3%), 5-10 ml/kg over 30 min, may be an alternative

to mannitol, especially if there is no initial response to mannitol. Intubation

may be required. When the patient is stabilized, a cranial CT or MRI scan

should be obtained to rule out other possible intracerebral causes of neuro-

logic deterioration (~10% of cases), especially thrombosis or hemorrhage,

which may benefit from additional therapy. Since there is no way to com-

pletely avert the development of cerebral edema, and approximately 50% of

patients who develop cerebral edema suffer permanent neurologic deficit or

die, eliminating DKA should be the goal of public and professional awareness

campaigns.

INTERMEDIATE PATIENT CARE

Intravenous fluid and insulin should be continued until vital signs are normal,

acidosis has been corrected, nausea and vomiting have stopped, and the DKA

precipitating factor has been controlled.

When subcutaneous insulin is begun, three points should be considered.

n Because subcutaneous insulin takes effect more slowly than intravenous

insulin loses its effectiveness, the first subcutaneous insulin injection

should be given 1-2 h before stopping intravenous insulin infusion if

using regular insulin and should be 15-30 min if using rapid-acting insu-

lin. For basal insulin, release from IV insulin should be gradual (e.g., a

reduced dose of SC basal insulin begins at night and the patient is com-

pletely suspended from IV insulin in the morning).

n Extra short- or rapid-acting insulin, every 4-6 h for the first 24-72 h,

or an increase in basal insulin delivery with continuous subcutaneous

insulin infusion (CSII), should be used to meet the increased insulin

demands of continuing stress surrounding DKA, to overcome “glucose

toxicity,” and to facilitate rapid adjustment of the insulin dose to con-

trol blood glucose during this transition phase. The patient should be

carefully observed to prevent recurrence of acidosis in the transition

phase.

n The patient may remain mildly insulin resistant for several weeks, so the

dose of subcutaneous insulin may exceed the patient’s usual requirements.

148 Medical Management of Type 1 Diabetes

PREVENTIVE CARE

Most often, DKA can be prevented, given appropriate patient education

and prompt attention. All patients with type 1 diabetes should be performing

self-monitoring of blood glucose (SMBG) regularly or using CGM in addi-

tion to being able to perform urine or blood ketone testing when hyperglyce-

mic (>250 mg/dL [>13.9 mmol/L]) or sick. Patients must be taught how to give

appropriate corrective doses of insulin when they develop hyperglycemia. A

proven method of doing this is to use their previously prescribed correction bolus

formula and repeat the dose at 2-h intervals until hyperglycemia has cleared.

Patients on insulin pumps must know to change all their disposables, i.e., infu-

sion set, syringe, and insulin, at the first evidence of hyperglycemia (>250 mg/dL

[>13.9 mmol/L]) that is associated with ketones or does not respond to an initial

correction bolus.

Patients must contact their health care team as soon as they become ill or

have nausea and vomiting, fever, or persistent hyperglycemia and hyperketon-

uria. When contacted early, the physician is often able to treat impending DKA

successfully by prescribing frequent injections of short- or rapid-acting insulin

and by oral administration of fluids. It may also be possible to rehydrate and

adequately replace insulin in the doctor’s office or emergency room, thereby pre-

venting hospitalization.

However, when there is any doubt that the patient can be successfully treated

in the home, office, or emergency room, hospitalization is indicated.

Attempts are being made to decrease the rates of DKA at the time of diag-

nosis, particularly in children. In children, the rate of DKA at diagnosis varies

by age, with children under 2 years of age having the highest rates. Worldwide

studies have shown that DKA rates vary by country. But in general, the incidence

of DKA at diagnosis has been decreasing. This decrease in DKA is likely due to a

number of factors, including increasing public and professional awareness about

the signs and symptoms of diabetes and the need for early diagnosis. In Parma,

Italy, a public awareness campaign conducted with physicians and schools, essen-

tially eliminated DKA at diabetes onset in children. In the US, it has been shown

that genetic screening combined with monitoring for signs of b-cell autoimmu-

nity has decreased the severity of illness at diagnosis.

CONCLUSION

The pathophysiology of DKA can be understood in the context of insulin

deficiency and excessive counterregulatory hormones, combining their effects to

produce a severe state of life-threatening metabolic decompensation. Insulin, flu-

ids, and electrolytes, given judiciously under appropriate guidelines in a hospital

setting, form the cornerstone of treatment. A precipitating event such as infec-

tion, infarction, or accidental or deliberate omission of insulin must be identified

and treated. All efforts at prevention should be employed with patients, as well as

with the public, so that DKA at diagnosis and in those with known diabetes can

eventually be eradicated.

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149

BIBLIOGRAPHY

American Diabetes Association: Hyperglycemic crises in patients with diabetes

mellitus (Position Statement). Diabetes Care 27 (Suppl. 1):S94-S102, 2004

Barker JM, Goehrig SH, Barriga K, Hoffman M, Slover R, Eisenbarth GS,

Norris JM, Klingensmith GJ, Rewers M: Clinical characteristics of children

diagnosed with type 1 diabetes through intensive screening and follow-up.

Diabetes Care 27:1399-1404, 2004

Dunger DE: European society for pediatric endocrinology and the Lawson

Wilkins pediatric endocrine society consensus statement on diabetic keto-

acidosis. Pediatrics 113:33-40, 2004

Glaser N, Barnett P, McCaslin I, Nelson D, Trainor J, Louie J, Kaufman FR,

Quayle K, Roback M, Malley R, Kuppermann N: Risk factors for cerebral

edema in children with diabetic ketoacidosis. N Engl J Med 344:264-269, 2001

Glaser N: Cerebral injury and cerebral edema in children with diabetic ketoaci-

dosis: could cerebral ischemia and reperfusion injury be involved? Pediatric

Diabetes 10:534-554, 2009

Kaufman FR, Halvorson M: The treatment and prevention of diabetic keto

acidosis in children and adolescents with type 1 diabetes. Pediatr Ann

28:576-582, 1999

Kitabchi AE, Umpierrez GE, Murphy MB, Barrett EJ, Kreisberg RA,

Malone JI, Wall BM: Management of hyperglycemic crises in patients with

diabetes mellitus (Technical Review). Ðiabetes Care 24:131-153, 2001

Kraut JA, Kurtz I: Use of base in the treatment of severe acidemic states. Am J

Kidney Dis 38:703-727, 2001

Larsson HE, Vehik K, Bell R, Dabelea D, Dolan L, Pihoker C, Knip M, Veijola R,

Lindblad B, Samuelsson U, Holl R, Haller MJ, on behalf of the TEDDY Study

Group, SEARCH Study Group, DVP Study Group, and Finnish Diabetes

Registry Study Group: Reduced prevalence of diabetic ketoacidosis at diagnosis

of type 1 diabetes in young children participating in longitudinal follow-up.

Diabetes Care 34:2347-2352, 2011

Marcin JP, Glaser N, Barnett P, McCaslin I, Nelson D, Trainor J, Louie J,

Kaufman FR, Quayle K, Roback M, Malley R, Kuppermann N: Factors

associated with adverse outcomes in children with diabetic ketoacidosis-

related cerebral edema. J Pediatr 141:793-797, 2002

Vanelli M, Chiari G, Ghizzoni L, Costi G, Giacalone T, Chiarelli F: Effective-

ness of a prevention program for diabetic ketoacidosis in children: an 8-year

study in schools and private practices. Diabetes Care 22:7-9, 1999

Viallon A, Zeni F, Lafond P, Venet C, Tardy B, Page Y, Bertrand JC: Does

bicarbonate therapy improve the management of severe diabetic ketoacido-

sis? Crit Care Med 27:2690-2693, 1999

Wolfsdorf J, Craig ME, Daneman D, Dunger D, Edge J, Lee W, Rosenbloom A,

Sperling M, and Hanas R :Diabetic ketoacidosis in children and adolescents

with diabetes. Pediatric Diabetes 10 (Suppl. 12):118-133, 2009

150 Medical Management of Type 1 Diabetes

HYPOGLYCEMIA

he precise blood glucose level at which patients develop symptoms of

hypoglycemia is difficult to define, but generally, symptoms do not occur

until blood glucose is <50-60 mg/dL (<2.7-3.3 mmol/L). Clinical hypogly-

cemia is the occurrence of typical autonomic and/or neuroglycopenic symptoms

with low blood glucose levels, and its symptoms are relieved by the administra-

tion of carbohydrate. Because of its sporadic and somewhat unpredictable nature

and because of the need for rapid treatment, hypoglycemia is often self-diagnosed

on the basis of predominantly autonomic symptoms and may be treated without

documentation of the blood glucose level.

PATHOPHYSIOLOGY

Hypoglycemia occurs when there is an imbalance between the rate of glucose

removal from the circulation (e.g., uptake into muscle) and the rate of glucose

entry into the circulation (e.g., release of glucose from the liver or ingestion of

nutrients). Clinically, this most often occurs when there is one of the following:

n a relative excess of insulin (which inhibits hepatic glucose production and

stimulates glucose utilization by muscle and adipose tissue)

n a decrease or delay in food intake (which decreases the availability of

dietary carbohydrate or gluconeogenic precursors)

n an increase in the level of exercise (which accelerates glucose utilization

by muscle)

In individuals without diabetes, as the glucose level declines below normal

(typically to 50-60 mg/dL [2.7-3.3 mmol/L]), a complex series of neuroendocrine

events occur that raise the plasma glucose concentration back toward normal.

Glucagon and epinephrine are thought to be the most important counterregula-

tory hormones in this process because of their prompt secretion and potent abil-

ity to stimulate the release of glucose from the liver. In addition, epinephrine can

contribute to glucose recovery by reducing glucose uptake into insulin-sensitive

tissues, and it is responsible for many of the autonomic warning symptoms of

hypoglycemia (see below). The other major counterregulatory hormones—cor-

tisol and growth hormone—generally are released more slowly than glucagon

and epinephrine and appear to have a more permissive role in glucose recovery.

Finally, endogenous insulin secretion is typically inhibited by hypoglycemia, also

facilitating the rise in plasma glucose levels.

In contrast, the patient with type 1 diabetes has several abnormalities in this

feedback system. First, the secretion of glucagon typically becomes deficient

within the first 2-5 years of diabetes. Second, with more prolonged duration of

the disease, epinephrine secretion may also be impaired as a result of the devel-

opment of subclinical autonomic neuropathy. Epinephrine secretory thresholds

can also be lowered by antecedent hypoglycemia or by tight glycemic control,

with these effects being reversible. Finally, the rate of absorption of insulin from

a subcutaneous depot is not regulated by normal homeostatic mechanisms, such

as nutrient availability, and thus, it continues despite the presence of ongoing

hypoglycemia. The combination of these and other factors makes the patient

Special Situations

151

with type 1 diabetes particularly susceptible to the frequent development of

hypoglycemia.

MILD, MODERATE, AND SEVERE HYPOGLYCEMIA

Symptoms of Mild Hypoglycemia

Mild low blood glucose reactions usually consist of tremors, palpitations,

sweating, blurred vision, mood variations, difficulty with auditory processing, and

excessive hunger. These symptoms are mostly mediated through the autonomic

(adrenergic) nervous system. Major cognitive deficits usually do not accompany

mild reactions, so patients are generally capable of self-treatment. These mild

symptoms respond within 10-15 min after oral ingestion of 10-15 g carbohydrate.

Signs and Symptoms of Moderate Hypoglycemia

Moderate low blood glucose reactions include neuroglycopenic as well

as autonomic signs and symptoms, e.g., headache, mood changes, irritability,

decreased attentiveness, and drowsiness. Because of confusion, impaired judg-

ment, and/or weakness, patients may require assistance in treating themselves.

Moderate reactions produce longer-lasting and somewhat more severe symptoms

and often require a second dose of carbohydrate.

Signs and Symptoms of Severe Hypoglycemia

Severe low blood glucose reactions are characterized by unresponsiveness,

combativeness, unconsciousness, or seizures and typically require assistance from

another individual for appropriate treatment. Approximately 5-10% of type 1 dia-

betes patients suffer at least one severe reaction each year that requires emergency

measures such as parenteral glucagon or intravenous glucose. Subjects who experi-

ence a hypoglycemic seizure with severe hypoglycemia are at risk for recurrence.

Potential Effects of Hypoglycemia

Mild hypoglycemic reactions may produce only minimal disruption of daily

activities. Hypoglycemia can cause hunger with consequent overeating, thus

contributing to obesity or hyperglycemia. Patients may experience cognitive

dysfunction and counterregulatory hormone impairment related to moderate

hypoglycemia even if they never reach a critically low blood glucose level if there

is a steep rate of fall. Cognitive dysfunction due to rapid rate of fall has been

shown to correlate with decreased counterregulatory hormone production.

In contrast, moderate and severe reactions may be seriously disabling in many

ways and their prevention is critical. Hypoglycemia that interferes with normal

thinking makes taking a school examination an impossible task; riding a bicycle,

driving a car, or operating dangerous machinery become potentially disastrous.

Repeated or prolonged episodes may cause irreparable damage to the central ner-

vous system in very young children. In adults, this is quite rare, and careful cogni-

tive testing of the DCCT cohort has shown no decrement in cognitive ability in

152 Medical Management of Type 1 Diabetes

intensively treated subjects or those with severe hypoglycemia. However, despite

the DCCT findings, there still remains a potential link between cognitive dys-

function and prolonged or repetitive hypoglycemic events. Severe hypoglycemia

is frightening and deleterious on the morale of the patient and family members,

a final reason for highlighting the need for prevention.

Some patients develop either an excessive fear of hypoglycemia or an inap-

propriate lack of concern. Fear of hypoglycemia can lead to chronic overeating,

undertreatment with insulin, or both. Maintaining very high blood glucose lev-

els to avoid hypoglycemia increases the risk of metabolic complications, includ-

ing DKA, and of chronic complications of diabetes. In contrast, patients with a

nonchalant attitude toward hypoglycemic reactions may maintain levels of blood

glucose that are too low, may take inadequate preventive or treatment steps, and

will consequently be at greater risk for recurrent severe hypoglycemia. These

patients can sometimes be identified by glycated hemoglobin (A1C) levels in the

normal range.

Antecedents of Severe Hypoglycemia

Certain circumstances favor development of prolonged, incapacitating,

and occasionally life-threatening hypoglycemia. Patients with hypoglycemia

unawareness are always at increased risk for severe reactions. The counterregu-

latory hormone response to hypoglycemia and the autonomic symptoms tend

to decrease after several years of diabetes so that neuroglycopenic symptoms

become the first manifestation for many patients. b-Blockers, methylxanithines,

selective serotonin reuptake inhibitors (SSRIs), and certain other medications

may also diminish early warning signs.

Hypoglycemia occurs more frequently at night, and it is more prolonged than

realized by most adults and children with type 1 diabetes. Hypoglycemia has been

described to occur during 8.5% of nights. The duration of hypoglycemia was >2 h

on 23% of nights with hypoglycemia. Risk factors for nocturnal hypoglycemia are

lower A1C and the occurrence of prior nocturnal hypoglycemia, but not age or

insulin treatment with CSII versus MDI. The predictors of severe hypoglycemia

are a prior severe episode in the preceding 6 months and being female. Studies

have also shown that hypoglycemia begets hypoglycemia. In studies done with

CGM, increased CGM readings <70 mg/dL and greater area under the hypogly-

cemic threshold increase the risk for severe hypoglycemia.

Intensive insulin therapy also increases the risk of asymptomatic hypogly-

cemia. Although the increased frequency of low glucose levels can be atŧributed

partly to the more stringent treatment goals associated with intensive regimens, it

is now apparent that physiologic alterations occur in the patient’s ability to secrete

counterregulatory hormones, and thus, the ability to recognize and recover from

hypoglycemia is clearly impaired. As few as two moderate episodes of hypogly-

cemia can blunt counterregulatory hormones. These observations emphasize the

importance of SMBG and CGM in such patients to detect and prevent these

asymptomatic reactions.

Delaying treatment of mild hypoglycemia can lead to more severe hypogly-

cemia as glucose stores are depleted from antecedent episodes. Because early

autonomic warning signs such as headache, hunger, mood or behavior changes,

Special Situations

153

or weakness are not specific to hypoglycemia, they are frequently misinterpreted

or overlooked. This is especially likely if the patient’s attention is directed else-

where, which may occur during strenuous activity. Hypoglycemia during sleep is

particularly difficult to detect as the counterregulatory hormones are suppressed

during sleep and therefore do not provide detectable symptoms. The patient

should be questioned for the presence of nightmares or nocturnal diaphoresis,

and family members should be alert to unusual sounds or activity during the

patient’s sleep.

COMMON CAUSES OF HYPOGLYCEMIA

The factors precipitating an episode of hypoglycemia can often be identified by

looking back over the events of several hours preceding the reactions (Table 4.5).

Inadvertent or deliberate errors in insulin dose are a frequent cause of hypo-

glycemia; other causes are changes in timing or schedule of insulin administration

or meals. For example, sleeping later than usual for patients on fixed regimens is

potentially dangerous because it disrupts the balance and timing between insu-

lin and food. Changing insulin type from a short- to rapid-acting preparation

or changing the insulin regimen can cause hypoglycemia because of more rapid

absorption or other factors.

Vigorous unexpected exercise or activity is commonly associated with hypo-

glycemia. Aerobic exercise of prolonged duration or increased intensity can cause

hypoglycemia up to 17 h after the activity ends or even the next day.

Alcohol, marijuana, or other drugs often mask a patient’s awareness of hypogly-

cemia in its earliest stages. By inhibiting the liver’s gluconeogenic capacity, alcohol

also prevents the body’s normal ability to provide glucose and restore low glucose

Table 4.5 Common Causes of Hypoglycemia

Insulin errors (inadvertent or deliberate)

Nutrition

n Reversal of morning and evening dosage

n Omitted or inadequate amounts of food

n Reversal of short- or rapid- and

n Timing errors: late snacks or meals

intermediate- or long-acting insulin

Exercise

n Improper timing of insulin in relation to

food

n Unplanned activity

n Excessive insulin dosage

n Prolonged duration or increased intensity

of activity

Intensive insulin therapy

Alcohol and drugs

Erratic or altered absorption of insulin

n Impaired hepatic gluconeogenesis asso-

n More rapid absorption from exercising

ciated with alcohol intake

limbs

n Impaired mentation associated with alco-

n Unpredictable absorption from hypertro-

hol, marijuana, or other illicit drugs

phied injection sites

Changing insulin preparations or

regimens

154 Medical Management of Type 1 Diabetes

levels toward normal. Some of the most severe hypoglycemic reactions occur during

or after parties because the combination of physical activity and the use of alcohol or

drugs can mask recognition of the problem and prevent the usual self-correction of

hypoglycemia. Drugs used for treatment of depression are linked with increased risk

for hypoglycemia. Several other drugs including levothyroxine (liver impairment) and

ACE inhibitors are also correlated with more insulin sensitivity and hypoglycemia.

Sulfonylureas, and other antihyperglycemic drugs, such as pramlintide, used in con-

cert with insulin increase risk for hypoglycemia.

Anticipating and Preventing Hypoglycemia

Once a situation that leads to hypoglycemia is identified, adjustments can

often be made to prevent future episodes.

Sleeping late. Although most patients on regimens of multiple daily injec-

tions can safely sleep an extra 30-60 min without particular adjustments, patients

who oversleep more than 1 h may need to plan in advance to alter insulin or

food intake. For example, if sleeping late is anticipated, a 10-15% reduction of

intermediate- or long-acting insulin on the previous evening is an effective means

of preventing hypoglycemia. However, it may also lead to excessive morning

hyperglycemia. When the patient awakens, the entire day’s schedule of insulin

and meals is advanced in time. Even the next day’s schedule may be affected. All

patients should be cautioned against awakening and taking insulin without eating

and then resuming sleep. However, awakening early, performing a blood glu-

cose test, administering insulin, eating breakfast, and then going back to sleep is

generally safe. Patients on insulin pumps, and many on long-acting analogs, may

be able to sleep late without a problem if their basal insulin doses are appropriate.

Before doing so, it would be wise to check the basal rate periodically by skipping

or delaying breakfast and observing the glucose changes every 2 h by SMBG.

Exercise. To compensate for increased caloric needs of exercise, increased

absorption of insulin from exercising muscles, and increased insulin sensitiv-

ity induced by extra activity, several strategies to prevent hypoglycemia can be

employed. Most important, the exercising patient should always have a source of

short-acting carbohydrate immediately available.

If early signs of hypoglycemia develop during exercise, the exercise should

be halted and an appropriate amount of carbohydrate eaten (Table 2.6). If simi-

lar exercise has previously resulted in hypoglycemia, patients can anticipate and

prevent it by snacking before, during, or after exercise, depending on when the

episode occurred. Decisions regarding the type and time of extra food can be

made based on SMBG.

Alternatively, hypoglycemia can be prevented by anticipatory adjustments

of insulin. For example, if a patient usually takes short- or rapid-acting insulin

before breakfast but is planning to exercise after breakfast, the insulin dose can

be reduced by 10-20%. This strategy may be preferable for patients who do not

want to increase the size of a meal before exercise or who are overweight. Patients

on insulin pumps can remove their pumps or implement a decreased temporary

basal rate, with the percentage of the decrease depending on the severity and

duration of the exercise.

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155

Role of CSII

It is recommended for patients to switch from MDI to CSII if they are unable

to mitigate hypoglycemia. A meta-analysis of 22 randomized controlled trials and

before/after studies confirmed that both A1C level and rate of severe hypoglyce-

mia were significantly lower with CSII compared to MDI. The greater improve-

ments from CSII in reducing or preventing severe hypoglycemia were in those

with the highest initial rates of hypoglycemia, lower A1C values, younger age,

shorter duration of diabetes and more frequent use of SMBG. Reports of non-

randomized clinic experiences have shown improved glycemic control without

increased risk of severe hypoglycemia when patients are switched from MDI

to CSII, and with the positive benefit sustained for up to 8 years. In addition,

improvement in hypoglycemia unawareness has been reported with CSII.

Role of SMBG and Continuous Glucose Monitoring

The availability of SMBG has made the detection and treatment of hypogly-

cemia practical, even in the subclinical range. Therefore, the frequency of SMBG

should be increased in patients with recurrent hypoglycemia. The addition of

continuous glucose monitoring (CGM), with its frequent testing and alarms for

low or rapidly decreasing glucose, has demonstrated the ability to further reduce

hypoglycemia. Changes in insulin injection, eating or exercise schedules, travel,

and other activities recognized as contributors to hypoglycemia call for increased

frequency of monitoring. Patients should be instructed to treat asymptomatic

hypoglycemia detected by SMBG or continuous monitors.

CGM is able to alert at hypoglycemic thresholds, with rapid rate of change

and with a predictive horizon, allowing the patient to prevent or reduce the time

spent in hypoglycemia. A short-term trial using CGM showed that time spent in

hypoglycemia decreased by 21% in subjects using real-time CGM compared to

controls. Nocturnal hypoglycemia was also significantly reduced, despite that fact

that it has been shown that many people sleep through the hypoglycemia alarms.

Long-term studies with CGM have shown that it results in a “relative” reduction

in hypoglycemia. This occurs because it is expected that as A1C levels decrease,

hypoglycemia, including severe hypoglycemia, will increase. But this has not been

the case, and lower A1C levels have not been associated with increasing hypogly-

cemia during CGM usage.

Attempts have been made to develop algorithms to predict risk of severe

hypoglycemia. These take into account the A1C, hypoglycemia unawareness,

ability to mount an autonomic response as glucose levels fall, and the frequency

and extent of recent low blood glucose levels on SMBG.

TREATMENT

Mild Hypoglycemic Reactions

For mild reactions, ingesting 15-20 g carbohydrate works quickly to

increase the blood glucose and stop classic symptoms. Several sources of

short-acting carbohydrate exist. Employing premeasured glucose products

156 Medical Management of Type 1 Diabetes

instead of juice or food is recommended because patients have a tendency to

consume >15 g of juice or food when they have symptomatic hypoglycemia, and

also because additional calories from fat or protein may cause weight gain.

Hypoglycemic reactions that occur during the night should be treated ini-

tially with 15-20 g carbohydrate and repeated if needed to treat hypoglycemia.

People have often been instructed to combine carbohydrate with protein to pre-

vent further hypoglycemia during the night; however, research does not show

that the addition of protein in the treatment of hypoglycemia sustains blood glu-

cose longer than carbohydrate alone. Having a larger snack does make sense,

including during the day if the next planned meal is >1-2 h away.

Commercially available glucose tablets have the added benefit of being pre-

measured to help prevent overtreatment. Glucose gels or small tubes of cake

frosting are convenient for children or patients who are uncooperative when

hypoglycemic. Chocolate and ice cream should be avoided for treating acute

hypoglycemia because the fat content retards absorption of available sugar and

could contribute to weight gain from ingestion of unnecessary calories.

Because there is always a risk that mild hypoglycemia will progress to a

more severe reaction, all episodes must be treated promptly and patients must

test again in 15 min to insure that they are normoglycemic. Treatment and

follow-up testing should be repeated if hypoglycemia persists. Patients should

be instructed never to continue driving when they begin to experience

hypoglycemia. They should stop, treat the hypoglycemia, and wait 15 min to

do SMBG, repeating as needed to ensure full recovery before they resume driv-

ing. Patients with type 1 diabetes should always have with them their meter and

glucose products with which to treat hypoglycemia. Evaluation of the effect of

nonsevere hypoglycemia on work productivity has shown that it is associated

with substantial economic consequences. Lost productivity was estimated to be

8.3-15.9 h of lost work time per month, and, therefore, strategies to reduce even

mild hypoglycemia could have a major positive impact on lost work productivity

for people with diabetes and their employers.

Moderate Hypoglycemia

Individuals with moderate reactions will often respond to the oral carbohy-

drates listed in Table 2.6 but may require more than one treatment and take

longer to fully recover. These patients may be alert but will frequently be unco-

operative or belligerent. Under such circumstances, if it becomes difficult to

cajole the patient to take oral carbohydrate, administration of subcutaneous or

intramuscular glucagon may be more appropriate.

Severe Hypoglycemia

Patients with impaired consciousness or an inability to swallow may aspi-

rate and should not be treated with oral carbohydrate. These patients require

either parenteral glucagon or intravenous glucose. If these are not available,

glucose gels, applied between the patient’s cheek and gum, may be of some

help.

Special Situations

157

Generally, clinical improvement should occur within 10-15 min after gluca-

gon injection and within 1-5 min of intravenous glucose administration. How-

ever, if hypoglycemia was prolonged or extremely severe, complete recovery

of normal mental function may not occur for hours to days. Repeated boluses

of intravenous glucose do not hasten recovery unless blood glucose measure-

ments show persistent hypoglycemia. If the hypoglycemic event was associated

with convulsions, the postictal period may be associated with severe headaches,

lethargy, amnesia, or vomiting. Decreased muscle control may also be seen and

requires medical evaluation if it persists.

Glucagon. The dose of glucagon needed to treat moderate or severe hypogly-

cemia for a child <5 years old is 0.25-0.50 mg; for an older child (age 5-10 years),

0.50-1 mg; and for those >10 years old, 1 mg. Glucagon should be given intra-

muscularly or subcutaneously in the deltoid or anterior thigh region. For chil-

dren, parents and school or day care providers, and for adults, roommates or

spouses should be taught how to mix, draw up, and administer glucagon so that

they are properly prepared for emergency situations. Kits that include a syringe

prefilled with diluting fluid are available. For mild or moderate hypoglycemia that

is associated with nausea or vomiting, administration of a low dose of glucagon

should be considered. In general, the dose is 1 unit per year of age up to about

15-20 units. This can be administered subcutaneously via normal 30-50 unit

syringe, rather than the intramuscular syringe provided with the kit. Full doses

of glucagon cause nausea or vomiting after recovery from hypoglycemia in some

patients.

Intravenous glucose. If medical staff and equipment are available, intravenous

glucose should be given as a primary treatment in preference to glucagon. The

usual dose is 10-25 g administered as 50% dextrose over 1-3 min. A useful for-

mula for giving 50% dextrose in the hospital is

cc of D50 = (100 - blood glucose mg/dL) × 0.4 ([5.5 - glucose mmol/L] × 0.4).

The dose can be titrated according to the patient’s response. After the bolus

injection, intravenous glucose (5-10 g/h) should be continued until the patient

has fully recovered and is able to eat.

HYPOGLYCEMIA UNAWARENESS

In the Diabetes Control and Complications Trial (DCCT), about one-third

of all episodes of severe hypoglycemia seen during waking hours in intensively

treated patients were not accompanied by sufficient signs or symptoms so that

patients could effectively prevent neuroglycopenia. In the past, hypoglycemia

without warning was viewed as a rare condition associated with advanced auto-

nomic neuropathy. This concept is incorrect. Forms of hypoglycemia without

warning can occur in recently diagnosed patients, particularly in patients with

repeated episodes of recent hypoglycemia and low A1C levels. Repeated episodes

of hypoglycemia cause two problems. First, they blunt hormonal defense mecha-

nisms that prevent hypoglycemia. Second, they lower the level at which early

hypoglycemic symptoms are perceived.

158 Medical Management of Type 1 Diabetes

The key clinical issue is that patients need to be reminded that the absence

of symptoms of hypoglycemia when glucose level is <55 mg/dL (<3.1 mmol/L)

should prompt consultation with their diabetes team and increased vigilance.

Frequent blood glucose monitoring, particularly before driving and after strenu-

ous exercise, is recommended. Evidence suggests that hypoglycemia unawareness

can be reversed by intensive education and self-management training and efforts

that successfully avoid hypoglycemia. These efforts may include adapting slightly

higher blood glucose targets before meals and during the night (e.g., lower target

to >100 mg/dL [>5.5 mmol/L]) and self-management training to help detect and

respond to subtle early signs of hypoglycemia. Continuous glucose monitors with

alarms that predict hypoglycemia have also been shown to help reinstate hypogly-

cemia awareness and the epinephrine response to subsequent hypoglycemia. This

suggests that real-time CGM might be a useful tool to reverse the hypoglycemia

unawareness associated with type 1 diabetes.

HYPOGLYCEMIA WITH SUBSEQUENT HYPERGLYCEMIA

Hypoglycemia followed by “rebound” hyperglycemia, also called the Som

ogyi effect, may complicate diabetes management in some patients. The phenom-

enon originates during hypoglycemia, with the secretion of counterregulatory

hormones (glucagon, epinephrine, growth hormone, and cortisol). This hor-

monal surge, together with decreasing insulin levels, leaves counterregulatory

hormones relatively unopposed. Hepatic glucose production is stimulated,

thereby raising blood glucose levels. These hormones may cause some insulin

resistance for a 12- to 48-h period. Moreover, excessive carbohydrate intake may

be a major contributor to rebound hyperglycemia.

The frequency of this phenomenon is debated, and studies suggest that it is

much less common than previously reported. It may follow nocturnal hypogly-

cemia, but it also may occur after hypoglycemia at any time. The hypoglycemic

event that precedes the rebound may not produce sufficient symptoms to make

it recognizable.

If rebound hyperglycemia goes unrecognized and insulin dosage is increased,

a cycle of overinsulinization may result, i.e., more hypoglycemia, more rebound

hyperglycemia, more insulin, more hypoglycemia. As a general rule, when hyper-

glycemia does not respond as expected to treatment adjustments, undetected

hypoglycemia and rebound hyperglycemia should be considered as a possible

explanation. Rather than increasing insulin dosage day after day, the clinician

who suspects rebound hyperglycemia should endeavor to detect (via SMBG) and

avoid the initiating hypoglycemic event.

Nocturnal hypoglycemia leading to fasting rebound hyperglycemia should

be investigated by measuring blood glucose levels between 2:00 and 4:00 a.m.

and again at 7:00 a.m. If blood glucose levels between 2:00 and 4:00 a.m. are

<50-60 mg/dL (<2.8-3.3 mmol/L) and those at 7:00 a.m. are >180-200 mg/dL

(>10.0-11.1 mmol/L), rebound hyperglycemia may have occurred. The increased

blood glucose level may be exacerbated by the waning effect of the previous dose

of intermediate-acting insulin or a prominent dawn phenomenon (see below). A

decrease in presupper intermediate-acting insulin or its deferral to ~9:00 p.m.

or a change to a basal analog (glargine) should prevent nocturnal hypoglycemia.

Special Situations

159

DAWN AND PREDAWN PHENOMENA

The amount of insulin required to normalize blood glucose during the night

is less in the predawn period (1:00-3:00 a.m.) than at dawn (5:00-8:00 a.m.). The

modest (20-40 mg/dL [1.1-2.2 mmol/L]) increase in plasma glucose commonly

seen in patients with type 1 diabetes given enough insulin to avoid hypoglycemia

in the predawn period is referred to as the dawn phenomenon. This increment

can be greater if insulin levels decline between the predawn and dawn periods

or if hypoglycemia occurs during the predawn period. The key clinical implica-

tion is that attempts to normalize prebreakfast glucose level (i.e., 70-115 mg/dL

[3.9-6.4 mmol/L]) often result in predawn hypoglycemia.

Several strategies can be used to identify and prevent nocturnal hypoglyce-

mia. These should include monitoring blood glucose at bedtime and at 2:00-

3:00 a.m., especially when insulin doses are being adjusted to correct prebreakfast

hyperglycemia or when blood glucose level is frequently in the normoglycemic

range before breakfast. In the DCCT, >50% of all episodes of severe hypogly-

cemia occurred during the night or when patients were asleep, even with the

use of long-acting insulin preparations given at night or insulin infusion pumps.

As a consequence, the median blood glucose before breakfast was 140 mg/dL

(7.8 mmol/L), and >75% of all prebreakfast values were over the upper target

range of 120 mg/dL (6.7 mmol/L). Adding extra food at bedtime (particularly

protein, which helps stimulate glucagon secretion) and giving insulin that does

not “peak” between 1:00 and 3:00 a.m. should be considered. Increasing the bed-

time snack is particularly important when nocturnal hypoglycemia is most likely

(e.g., after sustained exercise during the day or when prebedtime glucose is <100

mg/dL (<5.6 mmol/L). Among patients taking twice-daily injections, giving the

evening intermediate-acting insulin at bedtime or substituting it with long-acting

insulin may be effective. Changing the regimen to an insulin pump can also help

dramatically; the basal rate can be programmed to prevent nocturnal hypoglyce-

mia as well as cover the dawn rise of glucose.

CONCLUSION

Severe hypoglycemia can be life-threatening if not treated promptly. Even

mild and moderate hypoglycemia can cause both short- and long-term prob-

lems. All patients should be taught to be aware of the signs of hypoglycemia and

should be encouraged to use SMBG frequently to prevent and monitor episodes.

Continuous glucose monitoring may be a helpful adjunct in patients, particularly

with severe episodes and hypoglycemia unawareness. Patients should be aware to

change their regimen with exercise. All families, child care or school personnel,

and spouses or roommates of adults, should be taught how to use glucagon and

when to call for medical assistance.

BIBLIOGRAPHY

American Diabetes Association: Hypoglycemia and employment/licensure

(Position Statement). Diabetes Care 31 (Suppl. 1):S94, 2008

160 Medical Management of Type 1 Diabetes

Brod M, Christensen T, Thomsen TL, Bushnell DM: The impact of non-severe

hypoglycemic events on work productivity and diabetes management. Value

in Health 14:665-671; 2011

Cox DJ, Gonder-Frederick L, Ritterband L, Clarke W, Kovatchev BP: Predic-

tion of severe hypoglycemia. Diabetes Care 30:1370-1373, 2007

Cryer PE: Diverse causes of hypoglycemia-associated autonomic failure in dia-

betes. N Engl J Med 350:2272-2279, 2004

Cryer PE, Davis SN, Shamoon H: Hypoglycemia in diabetes (Technical

Review). Diabetes Care 26:1902-1912, 2003

DCCT Research Group: Hypoglycemia in the Diabetes Control and Complica-

tions Trial. Diabetes 46:271-286, 1997

Havlin CE, Cryer PE: Nocturnal hypoglycemia does not commonly result in

major morning hyperglycemia in patients with diabetes mellitus. Diabetes

Care 2:141-147, 1987

Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study

Group: Prolonged nocturnal hypoglycemia is common during 12 months of

continuous glucose monitoring in children and adults with type 1 diabetes.

Diabetes Care 33:1004-1008; 2010

Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study

Group: Factors predictive of severe hypoglycemia in type 1 diabetes. Diabe-

tes Care 34:586-590; 2011

Ly TT, Hewitt J, Davey RJ, Lim EM, Davis E, Jones TW: Improving epineph-

rine responses in hypoglycemia unawareness with real-time continuous glu-

cose monitoring in adolescents with type 1 diabetes. Diabetes Care 34:50-52,

2011

Perlmuter LC, Flanagan BP, Shah PH, Singh SP: glycemic control and hypogly-

cemia: is the loser the winner? Diabetes Care 31:2072-2076, 2008

Realsen JM, Chase HP: Recent advances in the prevention of hypoglycemia in

type 1 diabetes. Diabetes Technol Ther 13:1177-1186; 2011

Special Situations

161

PREGNANCY

ype 1 diabetes complicates ~0.1-0.2% of all pregnancies. During the last

40 years, perinatal outcome has improved remarkably in this high-risk

group. The perinatal mortality rate for women with diabetes who receive

optimal care now approaches that of the general obstetric population.

Management of the patient with type 1 diabetes during pregnancy ideally

involves an experienced medical management team, including the diabetologist or

endocrinologist, obstetrician or maternal-fetal specialist (perinatologist), pediatri-

cian or neonatologist, certified diabetes educator, dietitian, the patient, and her

partner. Experience indicates that the outcome for both mother and baby is gen-

erally more favorable when an experienced team is responsible for management

during pregnancy, delivery, and the perinatal period. When a team is not conve-

niently available, phone consultation with individual specialists is of paramount

importance. Pregnant women are usually highly motivated; therefore, this time is

ideal for teaching self-care skills they can use for the rest of their lives.

RISK FACTORS

What factors help quantify maternal and fetal risk in pregnancies complicated

by diabetes? Generally, risk factors fall into two categories: those relating to dia-

betes and its control and those relating to vascular complications. Thus, pregnan-

cies complicated by type 1 diabetes can be divided into two groups: women with

diabetes and women with diabetes and vascular complications.

Diabetes and Its Control

No longer does the onset and duration of diabetes influence the prognosis

for good perinatal outcome. Instead, the degree of glycemic control at concep-

tion and the presence or absence of secondary nephropathy, vasculopathy, micro-

albuminuria, and hypertension greatly influence the prognosis for a favorable

outcome for the mother and the fetus. The quality of maternal glucose control

throughout pregnancy is also an important consideration. Poor blood glucose

control, including ketoacidosis, is associated with intrauterine death.

Vasculopathy

The greater the degree of vasculopathy, the greater the likelihood of a poor

outcome for mother and child. Nephropathy, particularly if associated with hyper-

tension, appears to bring the greatest hazards, increasing the risk of preeclamp-

sia, fetal growth retardation, and preterm delivery. Pregnancy can contribute to a

worsening of retinal disease in women with background or proliferative retinopa-

thy, especially in the presence of hypertension; women with active proliferative

retinopathy are at greatest risk for progression, but visual loss can be minimized

with laser therapy. Maternal deaths have been reported in patients with coronary

artery disease. Other prognostically bad signs during pregnancy include ketoaci-

dosis, pyelonephritis, preeclampsia, and poor clinic attendance or neglect.

162 Medical Management of Type 1 Diabetes

MATERNAL METABOLISM DURING PREGNANCY

During gestation, maternal metabolism adapts to provide the fetus with an

uninterrupted supply of fuel. During the 1st trimester of a normal pregnancy,

accelerated utilization of glucose by the developing fetus generally produces a

decrease in maternal glucose levels. In addition, pregnancy-associated nausea and

vomiting can result in a decrease in food consumption. As a result, women with

diabetes are prone to hypoglycemia in the 1st trimester and insulin requirements

may decrease. Later in gestation, insulin resistance produced by the changing

hormonal milieu typically results in an increase in insulin requirements.

In nondiabetic pregnant women, glucose levels are typically lower than those

in the nonpregnant state. In pregnancy, human placental lactogen, prolactin, and

progesterone alter maternal islet cell function, producing b-cell hyperplasia and

contributing to maternal hyperinsulinemia. In addition, maternal cortisol is ele-

vated during pregnancy, which potentiates glucose intolerance. Human placen-

tal lactogen (hPL), a growth hormone-like protein synthesized by the placental

syncytiotrophoblast, produces insulin resistance and augments maternal lipolysis.

As placental mass enlarges during pregnancy, hPL levels rise, allowing increased

maternal utilization of fats for energy and sparing of glucose for fetal consump-

tion. In late pregnancy, the progression of overnight maternal fasting ketosis is so

accelerated that delaying breakfast may result in significant ketonuria.

In pregnancy complicated by diabetes, periods of maternal hyperglycemia pro-

duce fetal hyperinsulinemia. Larger amounts of maternal amino acids and other

fuels also cross to the fetus. Elevated levels of maternal glucose and other nutrients

stimulate the fetal pancreas, resulting in b-cell hyperplasia and hyperinsulinemia.

This combination of fetal overnutrition and fetal hyperinsulinemia contributes to

macrosomia in the infant of the mother with diabetes. In a report describing a

40-year experience in women with type 1 diabetes in Scotland, despite a marked

decrease in perinatal mortality from 225 per 1,000 total births after 28 weeks in

the 1960s to 10 per 1,000 births in the 1990s, standardized birth weight (adjusted

for gender, gestational age, and parity) did not change, indicating that intrauter-

ine overgrowth of the fetus still occurred due to failure to completely normalize

maternal glycemia.

PRECONCEPTION CARE AND COUNSELING

To prevent early pregnancy loss and very costly congenital malformations

in infants of mothers with diabetes, optimal medical care and patient education

and training must begin before conception. This is best accomplished through

a multidisciplinary team comprised of a diabetologist, internist or family prac-

tice physician, obstetrician, diabetes educators, including a nurse and registered

dietitian, and other specialists as necessary. Ultimately, the woman with diabetes

must become the most active member of the team, calling on the other members

for specific guidance and expertise to help her toward her goal of a healthy preg-

nancy and offspring.

Because treatment of the patient with type 1 diabetes must begin before gesta-

tion, any regular visit to the physician by a reproductive-age woman, from ŧeenage

to middle age, should be considered a preconception visit (Table 4.6). These

Special Situations

163

Table 4.6 Care Before Conception

n Discuss contraceptive program

n Optimize glycemic control: A1C as close

n Establish database for perinatal risk

to normal as possible without significant

Assess vascular status:

hypoglycemia

Ophthalmologic examination

n Refer for medical nutrition therapy

ECG

n Determine immune status against rubella

Consider exercise stress test if

n Evaluate psychosocial setting

diabetes >20 year duration

Caution patient against smoking or

Urine albumin excretion

excessive alcohol

Creatinine clearance

Assess exercise program

Peripheral pulses

n Begin daily folate supplement (600 mg)

Assess glycemic control via A1C testing

Assess thyroid function: free T₄, TSH

level, antimicrosomal antibodies

contacts provide an important opportunity to discuss the patient’s contraceptive

needs and her thoughts and concerns about a future pregnancy and to establish

a database that can be used in assessing perinatal risk. Adolescents in particular

should be encouraged to discuss these issues routinely with members of the dia-

betes management team.

Important periodic assessments include measurements of blood pressure,

dilated eye examinations, and assessments of kidney function and urine albumin

excretion. Note that preexisting cardiovascular disease significantly increases

morbidity and mortality to the mother and should be considered in women of

childbearing age with long duration of diabetes. A1C testing should be performed

routinely and SMBG taught, if needed. Continuous glucose monitoring should

be considered. The desired outcome of glycemic control in the preconception

phase of care is to lower A1C (at least 6.1% to <7%, preferably as close to normal

as possible without risks) so as to achieve maximum fertility and optimal embryo

and fetal development. Poor glycemic control during the period of organogen-

esis (first 7 weeks after conception) significantly increases the risk of congenital

anomalies and early pregnancy loss. Since much of this period may pass before

the woman is aware she is pregnant, preconception planning and excellent glyce-

mic control are critical.

Immune status against rubella should also be checked before conception.

Consultation with a nutritionist and a review of the patient’s exercise program

are important. Daily folate supplementation (600 µg) should be advised. The

patient must understand that smoking and alcohol are strictly prohibited during

pregnancy.

Because pregnancy complicated by type 1 diabetes may cause emotional and

financial stress, it is essential to evaluate the psychosocial interactions of the

patient and her partner, their support network, and their financial resources.

Women with type 1 diabetes who are contemplating pregnancy often have

questions regarding its impact on their health and the possible consequences for

164 Medical Management of Type 1 Diabetes

the fetus. Some of the most commonly encountered questions, along with sug-

gested answers, are presented below.

Q. How will pregnancy affect my health and life expectancy?

A. Pregnancy is not generally life-threatening, but serious complications can occur

if glycemic control is not maintained during pregnancy. There is no evidence

that pregnancy shortens the lives of women with type 1 diabetes, except for

some with established coronary artery disease. However, women with diabetes

do face a higher risk for certain complications. If ketoacidosis occurs, there is

the additional threat of fetal death. Preeclampsia and preterm delivery of the

fetus by cesarean section are more common in women with diabetes.

Q. What effect will pregnancy have on diabetic nephropathy?

A. There is no evidence that pregnancy will permanently worsen diabetic

nephropathy, although a temporary increase in proteinuria and decrease in

creatinine clearance may occur. On the other hand, advanced nephropathy

may jeopardize both mother and infant, increasing the risk for early pre-

eclampsia requiring preterm delivery and/or a smaller-than-normal infant.

Factors that point in this direction include

n proteinuria >2 g/24 h

n creatinine clearance <50 ml/min or serum creatinine >2 mg/dL

n hypertension: >130/80 mmHg despite treatment

Q. What effect will pregnancy have on diabetic retinopathy?

A. Except for women with active proliferative retinopathy, pregnancy is usu-

ally an ophthalmologically stable period. Women without diabetic retinopa-

thy will not usually develop it during pregnancy. Very few women who have

background retinopathy at the start of pregnancy experience a worsening of

this condition and very rarely to a proliferative stage. Proliferative retinopa-

thy treated by laser photocoagulation and stable before pregnancy will gener-

ally remain so. In contrast, women with active proliferative retinopathy that

has not been treated with photocoagulation may experience a serious worsen-

ing of this complication during pregnancy. A dilated eye examination prior to

conception or in the first trimester is advised.

Q. Will the baby develop diabetes?

A. The infant is slightly more likely to develop type 1 diabetes later in life

because of maternal diabetes, but the risk is not very high, i.e., ~3-4%.

Q. Can I use birth control pills?

A. Young women without vascular complications may use a low-dose estrogen

(≤35 µg)/progestin oral contraceptive. Those with hypertension or vasculopa-

thy should use a progestin-only pill (or some other means of birth control).

Q. What effect will diabetes have on the baby?

A. The answer to this question appears to hinge largely on the mother’s blood

glucose control; generally, the better the diabetes control, the fewer the

Special Situations

165

Table 4.7 Techniques and Purpose of Fetal Assessments Used in Pregnant

Women with Preexisting Diabetes According to Gestational Age

Testing Modality

Timing

Comments

Ultrasound, transvaginal,

1st trimester

Important to confirm living fetus, establish

or transabdominal

gestational age and estimated due date as

• Crown-rump length

early as possible; elevated NT measurement

is associated with fetal Down Syndrome,

• Fetal cardiac activity

and specific congenital anomalies (cardiac

• Nuchal translucency

defects, diaphragmatic hernia, skeletal and

(NT) thickness at 12-13

neurologic abnormalities) more common in

weeks; couple with free

women with PDM

b-hCG, PAPP-A

Maternal serum marker

1st trimester

PDM is associated with an increased risk

screening

(with or without

of open neural tube defects (detected by

ultrasonic NT

2nd trimester triple or quad marker test, or

measurement)

MSAFP alone)

Second trimester

(triple¹or quad²

marker test, or

MSAFP alone)

Ultrasound, transabdominal

2nd trimester

Important to establish gestational age when

• Fetal biometric

this has not been done earlier in pregnancy;

measurements

detailed fetal anatomic examination and fetal

• Fetal anatomy

echocardiography should be considered in

all women with PDM, but particularly in those

at highest risk for congenital anomalies³

Ultrasound, transabdominal

3rd trimester

Following fetal growth by ultrasound exami-

• Fetal growth rate

nations at regular intervals may be warranted

(abdominal circumference

when a pregnancy is at risk for fetal growth

measurement reflects

restriction (hypertension or vascular compli-

fetal adiposity)

cations) or excessive fetal growth (poor gly-

• Amniotic fluid volume

cemic control), or in lower risk women when

a fundal height dates discrepancy is noted

Non-stress test (NST)

3rd trimester

Abnormal NST and BPP tests suggest pos-

sible decreased fetal oxygenation status, but

are affected by other factors. The optimal

testing regimen and the ideal time to initiate

testing are not known. However, women with

Biophysical profile (BPP)

3rd trimester

hypertensive disorders, vascular disease, or

evidence of fetal growth restriction should

begin testing earlier, with a frequency of

every 3-7 days

Amniotic fluid markers of

Before delivery in

Positive tests suggest a low risk of RDA in

fetal lung maturity

indicated cases

the newborn infant⁴

¹Maternal serum α-fetoprotein (MSAFP), unconjugated estriol, chorionic gonadotropin

²All components of the triple marker test, plus inhibin

³Elevated 1st trimester hemoglobin A1C value, abnormal multiple marker results, abnormality suspected on

basic ultrasound study, or personal history of a prior birth affected by congenital anomalies

⁴RDS, respiratory distress syndrome

166 Medical Management of Type 1 Diabetes

complications. In the first weeks of pregnancy, poor diabetes control appears

to increase the occurrence of fetal malformations. Later, high blood glucose

levels may bring about other serious consequences. Because glucose crosses

from the mother to the fetus but insulin does not, high maternal glucose stim-

ulates the fetus to overproduce insulin, which may

n cause excessive fetal growth, which increases the risk of shoulder dystocia,

birth injury, and need for cesarean delivery

n prevent the baby’s lungs (and other organs) from maturing at a normal

pace

n give the baby serious hypoglycemia after birth, when it no longer receives

glucose from the mother

In addition, high glucose levels are associated with sudden unexplained fetal

death late in pregnancy. The incidence of preeclampsia is lowest in women with

optimal glycemic control and rises as A1C increases. Preeclampsia in women with

type 1 diabetes is also correlated with the presence of microalbuminuria.

CONGENITAL MALFORMATIONS: RISK AND DETECTION

The incidence of major congenital malformations in the offspring of women

with type 1 diabetes that is well controlled in the first trimester is similar to the

2-3% rate observed in the general population. However, the rate increases with

poorer glycemic control to as high as 20-25% among women with markedly

elevated A1C in the 1st trimester. Cardiac and neural tube defects are common

classes of malformation in these cases. Elevated A1C in the beginning weeks

of pregnancy and second-trimester hypertension have also been linked to early

delivery (pre 34 weeks).

Much evidence links such malformations with inadequate diabetes control

during embryogenesis (gestational week 3-7). The magnitude of risk for abnor-

malities increases proportionally to the degree of elevation of A1C during this

period. For this reason, patients should have as close to normal glycemic levels

as possible at conception and throughout the 1st trimester. All women of child-

bearing age should be made aware of these risks, and if pregnancy is considered,

they should be encouraged to use contraception until excellent glycemic control is

achieved (see Philosophy and Goals, page 27). The risk of fetal anomalies should

be reviewed at the first prenatal visit.

Table 4.8 Target Blood Glucose Levels in Pregnancy

Blood Glucose

Time of Measurement

(mg/dL [mmol/L])

Before breakfast

60-99 (3.3-5.4)

Before lunch, supper, and bedtime snack

60-99 (3.3-5.4)

1 h after meals

100-129 (5.4-7.1)

2:00-6:00 a.m.

60-99 (3.3-5.4)

A1C levels should be within the normal range for pregnancy.

Special Situations

167

Fetal anomalies associated with diabetic embryopathy can be detected pre-

natally in most cases. Ultasonography for nuchal translucency (possibly with 1st

trimester biochemical screening with pregnancy-associated plasma protein A and

b-human chorionic gonadotropin) should be offered at 11-13 weeks. At 16 weeks,

further evaluation for a potential fetal malformation should include a maternal

serum b-fetoprotein level, possibly combined with unconjugated estriol and cho-

rionic gonadotropin (“triple screen”) or additionally with inhibin (“quadruple

screen”). A detailed ultrasound examination of fetal anatomy should be done at

16-18 weeks. In women with high risk of fetal cardiac anomalies (such as those

with poor 1st trimester glycemic control), assessment of fetal cardiac structure by

echocardiography at 20 weeks should be considered. All of these studies require

interpretation by specialists experienced in prenatal diagnosis.

MATERNAL GLUCOSE CONTROL DURING PREGNANCY

Excellent control of maternal diabetes will reduce the risks of fetal demise,

excessive fetal growth, and delayed pulmonary maturation. During a nondiabetic

pregnancy, maternal plasma glucose rarely exceeds 100 mg/dL (5.6 mmol/L),

ranging from fasting levels of 60 mg/dL (3.3 mmol/L) to postprandial levels <120

mg/dL (<6.7 mmol/L). These values should be therapeutic objectives for preg-

nancies complicated by type 1 diabetes (Table 4.8).

Maintaining maternal glucose levels in this range throughout gestation is

difficult. During the 1st trimester, when morning sickness may be troublesome,

the risk of hypoglycemia is increased; hypoglycemia is most likely during the

night, when the mother is fasting but the fetus and placenta continue to consume

glucose. Severe hypoglycemia is three times more frequent in early pregnancy

(8-16 weeks) compared to the prepregnancy time period. In the 3rd trimester,

hypoglycemia decreases when insulin resistance from the counterregulatory hor-

mones of pregnancy is greatest. Insulin needs may rise 50-100% over the final

4-6 weeks, and the total insulin dose at the time of delivery may double or even

triple that of prepregnancy.

Monitoring Control

SMBG and CGM. During pregnancy, women with type 1 diabetes must use

SMBG to assess control. SMBG has been shown to decrease the need for hos-

pitalization and reduce the cost of care. Patients should monitor in the fasting

state, before each meal, and 1 h after meals. Testing at 2:00-3:00 a.m. is necessary

for most patients, particularly for those who are likely to experience nocturnal

hypoglycemia, those who have persistent fasting hyperglycemia, or those who are

using continuous subcutaneous insulin infusion. Continuous glucose monitoring

(CGM) can be used in pregnancy and may help diagnose high postprandial glu-

cose levels and nocturnal hypoglycemia that are missed with SMBG. The patient

should be instructed to self-adjust insulin and maintain a careful record of the

daily glucose and insulin values with comments about calorie intake and exercise.

Available data are too limited to permit specific recommendations regarding

exercise programs in pregnant women with diabetes, but in most women with

type 1 diabetes, the general recommendations for all pregnant women apply.

168 Medical Management of Type 1 Diabetes

A1C testing. A1C testing should be obtained at the patient’s first prenatal

visit to assess previous glycemic control. This test should be repeated every 4-6

weeks.

Ketone testing. Patients should be instructed to test for ketones any time

glucose levels exceed 200 mg/dL (11.1 mmol/L).

Insulin Regimen During Pregnancy

An insulin regimen tailored to the patient’s needs can be developed based on

SMBG or continuous glucose monitoring system (CGM) data, the meal plan, and

the exercise regimen. Almost all women will require preprandial rapid- or short-

acting insulin with a basal insulin. Although the basal insulins glargine and detemir

are FDA pregnancy category C, there have been reports of the use of insulin

glargine in pregnancy that have shown no increase in morbidity or macrosomia.

For women who are well controlled on a long-acting analog prior to pregnancy,

the theoretical benefit of switching to NPH insulin (which has a long track record

of safety in pregnancy) must be weighed against the risks of a deterioration in gly-

cemic control or increased number of hypoglycemic reactions with a change in

regimen. The greatest flexibility and control is provided by insulin pump therapy.

Some women may be controlled with a morning mixture of intermediate-

acting and rapid- or short-acting insulins, rapid- or short-acting insulin before

supper, and intermediate-acting insulin near bedtime. This regimen helps avoid

glycemic irregularities overnight, decreasing the likelihood of nocturnal hypogly-

cemia and providing effective prophylactic treatment for the dawn phenomenon

and/or the waning of the insulin effect in the early morning hours leading to

prebreakfast hyperglycemia. However, postlunch glucose levels may be difficult

to control without a prelunch injection of rapid- or short-acting insulin.

During pregnancy, most women prefer the flexibility of a four-injection

regimen: a mixture of intermediate-acting and rapid- or short-acting insulins at

breakfast, rapid- or short-acting insulin at lunch and supper, with an injection of

intermediate- or long-acting insulin at bedtime.

In general, if glucose levels remain elevated pre- or postmeal, the correspond-

ing insulin dose is increased by 10-20%. Although glycemic goals are lower,

strategies for titrating insulin doses are similar in pregnant women to those used

in non-pregnant adults (see Optimizing Blood Glucose Control, Chapter 3).

Insulin pump therapy. Pump therapy in pregnancy is best managed by a dia-

betes team with expertise in this form of therapy. Patients who have used insulin

pump therapy before gestation should continue on this program. Patients who

are not at goal either preconception or during pregnancy should be considered

for pump therapy.

Pump therapy in pregnancy offers several advantages over multiple daily

injections. Most important, quick titration of both basal insulin and bolus insulin

to achieve the stringent goals of pregnancy without hypoglycemia is relatively

easily accomplished. In times of morning sickness in the 1st trimester, the patient

can rely on her basal infusion and take the bolus postmeal once the food is con-

sumed. Boluses for snacks are also easily covered without the need of a separate

injection. Most pregnant women use at least 2-3 basal infusion rates per 24 h,

Special Situations

169

with an increased rate in the early morning hours to counteract the increased

release of the counterregulatory hormones, growth hormone, and cortisol later

in pregnancy. The pump also allows the nocturnal basal infusion to be decreased

early in pregnancy if needed to reduce the risk of hypoglycemia.

Pump therapy is not without risks during pregnancy. Most important, should

there be interruption of insulin delivery, rapid development of ketoacidosis may

occur. All pregnant patients on pumps must be instructed at each visit how to trou-

bleshoot hyperglycemia and change the infusion set and insulin reservoir if hyper-

glycemia (>200 mg/dL [>11.1 mmol/L]) does not respond to a correction bolus. In

addition, changing of the infusion site every 2 days is often needed in addition to

rotation of the sites away from the abdominal area in the 3rd trimester. Skin irritation

can be more common in pregnancy, and appropriate troubleshooting must be done.

NUTRITION NEEDS

The daily nutrition needs of pregnant women with type 1 diabetes should

be based on a nutrition assessment by a dietitian. SMBG results, ketone tests,

appetite, and weight gain can be a guide to developing and evaluating an indi-

vidualized meal plan.

For most patients, 10% of the calories should be consumed at breakfast, 30%

at lunch, and 30% at supper. The remaining 30% of calories can be distributed

among several snacks, particularly at bedtime snack to decrease the risk of noc-

turnal hypoglycemia. Additional snacks may be added if the patient anticipates an

increase in physical activity. Patients with persistently elevated midmorning glu-

cose levels should reduce the calorie and/or fat content of breakfast and redistrib-

ute the calories to lunch and supper. Fat can slow digestion, resulting in elevated

blood glucose levels later than when carbohydrate alone is eaten. The presence

of morning ketonuria with normal glucose levels indicates the need to increase

the calorie content of the bedtime snack or to consider adding a snack around

3:00 a.m. However, there is no evidence that starvation ketosis has an effect on

outcome. The calorie content of the meal plan may be reduced in women who

are obese, who demonstrate early excessive weight gain, or who have a seden-

tary lifestyle. Guidelines for calorie needs for women who begin pregnancy at a

desirable weight can be obtained from appropriate references (see also Nutrition,

page 98). Attention should be paid to providing sufficient intake of folate, in

the form of supplementation of 600 mg daily, calcium, other vitamins, and iron,

although these vitamins and minerals are important for all pregnant women and

not specific to women with diabetes.

OUTPATIENT CARE

Most women with type 1 diabetes may be managed as outpatients throughout

gestation. Some may benefit from early hospitalization to evaluate cardiovascular

and renal status and glucose control. Failure to maintain acceptable glucose lev-

els, worsening hypertension, or infectious complications, such as a viral illness or

pyelonephritis, may necessitate hospitalization. A urine culture should be ordered

in the 1st trimester, because up to 25% of type 1 diabetic women can have asymp-

tomatic urinary tract infections in the 1st trimester.

170 Medical Management of Type 1 Diabetes

Clinic visits can be scheduled at monthly intervals early in pregnancy if gly-

cemic control is good, and at 1- to 2-week intervals during the first trimester. At

each visit, the patient’s SMBG meter, log, or uploaded data should be reviewed,

problems with hyperglycemia and/or hypoglycemia discussed, and the patient’s

weight gain and blood pressure checked. The patient should also be instructed

to telephone the team promptly if there are any episodes of hypoglycemia

(<50 mg/dL [<2.8 mmol/L]) or hyperglycemia (>200 mg/dL [>11.1 mmol/L]) so

that appropriate immediate remedial action may be taken.

Throughout gestation, the physician coordinating the patient’s management

must communicate regularly with other members of the medical management

team. If background retinopathy has been detected, repeat ophthalmologic exam-

inations should be obtained in the 2nd or 3rd trimester; proliferative retinopa-

thy requires more intensive follow-up. If rapid normalization of blood glucose

is needed, then monthly visits to the ophthalmologist are necessary to treat any

development of neovascularization. Renal function studies, including creatinine

clearance and protein excretion, should be repeated in each trimester if baseline

values are abnormal.

Assessment of Fetal Condition

Significant advances have been made in the ability to assess fetal growth and

well-being. The detection of fetal malformations between 16 and 20 weeks is

discussed above (see Congenital Malformations: Risk and Detection, page 166).

In the 3rd trimester, attention should be directed toward the assessment of fetal

well-being, growth, and pulmonary maturation. Several approaches should be

used to assess fetal condition to prevent sudden intrauterine death, a catastrophe

most likely to occur during the final 4-6 weeks of gestation.

Patient self-assessment. Maternal monitoring of fetal activity has proved

to be a simple yet valuable screening approach in high-risk pregnancies. Daily

assessment of fetal movement may be started at 28 weeks’ gestation. The patient

counts fetal activity for several 30- to 60-min periods throughout the day or

records the time of day at which she has felt a total of 10 fetal movements. A

significant decrease in fetal activity demands further evaluation.

Nonstress test. The nonstress test (NST) is an ideal screening technique that

is easily performed in an outpatient setting and usually requires no more than

20 min. Fetal heart rate is recorded with an external heart rate monitor. A normal

response is the presence of two or more accelerations of at least 15 beats and last-

ing at least 15 s during 20 min of observation. This “reactive” test is considered a

reassuring finding. In a metabolically stable patient, a reactive NST will predict

fetal survival for up to 1 week.

The NST may be performed weekly after 28 weeks’ gestation and then twice

weekly at 32 weeks of gestation. Because normal fetal activity and a reactive

NST are rarely associated with an intra-uterine fetal death, the primary value

of surveillance is to allow the clinician to delay delivery safely while the fetus

gains further maturity. However, because the screening tests have significant

false-positive rates, an abnormal test, e.g., as a decrease in fetal activity, must be

further evaluated.

Special Situations

171

Biophysical profile. Some clinicians have turned to the biophysical profile

to assess fetal condition. The biophysical profile utilizes real-time ultrasound

to observe fetal activity, fetal breathing movements, amniotic fluid volume, and

fetal tone. Like the NST, the biophysical profile can usually be completed in

15 min and, if normal, indicates fetal well-being.

Assessment of Fetal Growth

Fetal growth assessment with serial ultrasound examinations may be war-

ranted during the 3rd trimester in women at risk for fetal growth restriction

(maternal hypertension or vasculopathy) or excessive fetal growth (poor glycemic

control), or in lower-risk women if there is a discrepancy between fundal height

and pregnancy dates. Delivery by cesarean section should be considered if the

ultrasound suggests excessive fetal size. In pregnancies complicated by diabetes,

an infant >4,000 g increases the risk of shoulder dystocia. At 20-22 weeks, an

anatomic ultrasound may help detect congenital malformations and a maternal

Doppler may be a good early assessment for preeclampsia.

The techniques utilized today for antepartum fetal surveillance permit most

patients to remain outside the hospital even during the final 4-6 weeks of gesta-

tion, as long as maternal control is acceptable and fetal evaluation is reassuring.

Nevertheless, hospitalization may be necessary if the patient has nephropathy

and/or hypertension, if she has not adhered to the regimen, or when fetal jeop-

ardy is suspected.

TIMING OF DELIVERY

In the past, preterm delivery was often elected to avoid the risk of intrauter-

ine fetal death. In many instances, such infants, although born alive, succumbed

to respiratory distress syndrome (RDS). An increased incidence of RDS due to the

combined effects of prematurity and diabetes, which may retard normal matura-

tion of pulmonary surfactant production, was observed in infants of mothers with

diabetes.

Today, delivery can be safely delayed until 38 weeks in most pregnancies com-

plicated by type 1 diabetes. Labor may then be induced after 38 weeks without

amniocentesis to confirm lung maturity, or the onset of spontaneous labor may

be awaited. Patients must continue excellent glycemic control, and all parameters

of antepartum fetal surveillance should remain normal.

In women who have vasculopathy, who have been in poor control, who have

had a prior stillbirth, or who have not adhered to the program of care, early elec-

tive delivery to prevent a late fetal death may be planned provided that fetal pul-

monary maturation has been confirmed by the analysis of amniotic fluid obtained

by amniocentesis. RDS is highly unlikely when the amniotic fluid lecithin-to-

sphingomyelin ratio is >2.0 and phosphatidylglycerol is present.

If the fetal lungs are immature, delivery may be postponed as long as the

results of fetal assessment remain reassuring. It is essential that the obstetrician

know the reliability of the analytical technique used for phospholipid analysis in

the reporting laboratory, particularly in pregnancies complicated by diabetes.

172 Medical Management of Type 1 Diabetes

Delivery despite fetal lung immaturity may be necessary when testing sug-

gests fetal compromise or if the pregnant patient develops preeclampsia, rapidly

worsening retinopathy, or renal failure. As is the case in nondiabetic pregnan-

cies, antenatal glucocorticoids are indicated to enhance lung maturity for preterm

delivery at 24-33 weeks’ gestation. There are no clinical trials specifically in dia-

betic pregnancies or in deliveries at 33-38 weeks if indices of fetal lung maturity

are abnormal. Administration of high-dose corticosteroids will cause hyperglyce-

mia in the diabetic mother, and this should be treated aggressively.

LABOR AND DELIVERY

The timing and site of delivery must be discussed and coordinated with the

neonatologists who are to be present. If delivery is anticipated and adequate

maternal or neonatal care cannot be provided, the patient should be transferred

to a hospital with an appropriately equipped nursery. Expert care is required to

deal with the various complications that may arise in the infant of the mother

with diabetes.

Intrapartum electronic monitoring of the fetal heart rate is mandatory. Labor

should be allowed to progress as long as cervical dilation and descent follow the

established curves for normal labor. Any evidence of an arrest pattern should alert

the physician to the possibility of cephalopelvic disproportion and fetal macrosomia.

Maternal Glucose Levels During Delivery

Maintenance of normal maternal glucose levels (60-100 mg/dL [3.3-

5.6 mmol/L]) during labor and delivery is important in eliminating hypoglycemia

for the mother and keeping both mother and child safe. Though a more recent

study shows a stronger correlation of maternal A1C during the second trimester

to neonatal hypoglycemia than maternal glucose levels during labor and delivery,

other studies show normal maternal glucose levels will reduce the risk of sub-

sequent neonatal hypoglycemia. A glucose and insulin infusion can be used to

maintain glucose levels in this range. Below are insulin infusion rates deemed safe

and effective in maintaining maternal glucose levels during labor. They are used

with a 10% dextrose solution at an 80 mL/h rate and with hourly capillary blood

glucose monitoring:

n Constant 1U/h with a BG level of 3.4-7.8 mmol/L (61-140 mg/dL)

n Increase to 1.5 U/h for BG of 7.8-10.0 mmol/L (140-180 mg/dL)

n Increase to 2 U/h for BG of 10.0-12.2 mmol/L (180-220 mg/dL)

n Increase to 3 U/h for BG above 12.2 mmol/L (220 mg/dL)

During active labor in most patients, insulin requirements typically decrease

substantially, with most patients requiring a reduction in their basal insulin. Glu-

cose levels should be determined hourly with SMBG or CGM techniques at the

bedside, because even small doses of insulin may produce hypoglycemia during

active labor. Adjustments in the delivery of insulin and/or glucose should be made

based on the glucose determinations. See Medical Management of Pregnancy Com-

plicated by Diabetes (see Bibliography, page 174).

Special Situations

173

If labor is electively induced or a cesarean section is planned, the procedure

should be scheduled for the early morning and the patient’s usual morning rapid-

or short-acting insulin dose withheld. Further glycemic control can be achieved if

the patient is fasting. If using an insulin pump, the basal insulin may be continued

at low rates with further decrease in the basal rate at the time of delivery to avoid

maternal hypoglycemia. Epidural anesthesia is preferred in patients scheduled for

cesarean section. After the operation has been completed, glucose levels should

be monitored every 1-2 h, and an intravenous solution containing 5% dextrose

should be continued. Because hPL and its counterregulatory actions fall rapidly

after removal of the placenta, no insulin may be required for the remainder of the

day if the previous injection of the long-acting insulin is still in effect.

POSTPARTUM CARE

In the immediate postpartum period, the patient’s insulin requirements

are usually lower than her prepregnancy needs. The antepartum objective of

physiologic glycemic control is usually relaxed at this time and returned to pre

pregnancy levels (90-130 mg/dL [5.0-7.2 mmol/L]. If the patient uses an insulin

pump, the basal rate should be reset at or below the prepregnancy rate. Breast-

feeding is encouraged. The meal plan for the breast-feeding mother should be

30-37 kcal/kg desirable body weight.

If the patient delivered vaginally, and if glucose levels are ≥200 mg/dL,

short-acting insulin should be administered as necessary as a correction bolus

based on prepregnancy requirements, or an insulin infusion can be continued

or started. Once eating, the insulin regimen can be resumed but lowered to

or below the prepregnancy insulin requirements. The doses should be adjusted

based on SMBG.

In patients who have undergone a cesarean section, minimal insulin may be

required for the first 2 postoperative days because calorie intake is limited. By day

2 or 3, the prepregnancy insulin schedule may be resumed and the dose adjusted

using SMBG. Further adjustment of insulin needs in the postpartum period

should always be individualized based on SMBG results.

FAMILY PLANNING AND CONTRACEPTION

Family planning and contraception must be reviewed with the patient dur-

ing the postpartum period. Although oral contraceptives are the most effective

method available, the increased risk of thromboembolic disease and vasculopa-

thy require that combined estrogen/progestin oral contraceptive preparations

be used with caution, and then only in women who have no macrovascular

diseases or diabetes for less than 20 years. For these women, only low-dose

(≤35 µg) estrogen agents or intrauterine devices (IUDs) should be prescribed.

Combination agents are contraindicated in women with hypertension or vas-

culopathy, who may be offered a progestin-only pill or nonhormonal contra-

ception instead. After >20 years of diabetes, women, regardless of presence

of macrovascular disease, retinopathy, nephropathy, or neuropathy or not,

should be removed from a combination hormone ŧreatment and placed on

174 Medical Management of Type 1 Diabetes

a nonhormone treatment or an IUD. Condoms should be encouraged in all

patients as a secondary/dual form of contraception as they also help protect

against sexually transmitted diseases.

Motivated patients may do well with one of the barrier methods of contra-

ception, such as the diaphragm, although their efficacy is significantly lower than

that of oral contraceptives. Sterilization of the patient or her partner should be

discussed with the patient when she has completed her family or if she has seri-

ous vasculopathy. All contraception discussions should be in accordance with the

patient’s religious beliefs.

CONCLUSION

Advances in prenatal care and diagnosis, fetal surveillance, and perinatal care

have markedly improved maternal and fetal well-being in pregnancy complicated by

diabetes. Meticulous metabolic control before and during pregnancy holds the key to

a successful outcome and to minimizing fetal malformations or perinatal complica-

tions. A team approach is more likely to achieve a desirable result.

BIBLIOGRAPHY

American Diabetes Association: Preconception care of women with diabetes

(Position Statement). Diabetes Care 27 (Suppl. 1):S76-S78, 2004

American Diabetes Association: Medical Management of Pregnancy Complicated by

Diabetes. 4th ed. Jovanovic L, Ed. Alexandria, VA, American Diabetes Asso-

ciation, 2008

Codner E, Soto N, Merino PM: Review of puberty, contraception, and preg-

nancy in adolescents with type 1 diabetes. Pediatric Diabetes. http://dx.doi

.org/10.1111/j.1399-5448.2011.00825.x, 2011

Jensen DM, Beck-Nielsen H, Damm P, Westergaard JG, Ovesen P, Moeller M,

Mølsted-Pedersen L, Mathiesen ER: Microalbumenuria, preeclampsia and

preterm delivery in pregnant women with type 1 diabetes. Diabetes Care 33:

90-94, 2010

Johnstone FD, Lindsay RS, Steel J: Type 1 diabetes and pregnancy: trends in

birth weight over 40 years at a single clinic. Obstet Gynecol 107:1297-1302,

2006

Jovanovic L, Peterson CM, Reed GF, Metzger BE, Mills JL, Knopp RH, Aar-

ons JH: Maternal postprandial glucose levels and infant birth weight: the

Diabetes in Early Pregnancy Study. The National Institute of Child Health

and Human Development—Diabetes in Early Pregnancy Study. Am J Obstet

Gynecol 164:103-111,1991

Lepercq J, Abbou H, Agostini C, Toubas F, Francoual C, Velho G, Dubois-

Laforgue D, Timsit J: A standardized protocol to achieve normoglycaemia

during labour and delivery in women with type 1 diabetes. Diabetes and

Metabolism 34:33-37, 2008

176 Medical Management of Type 1 Diabetes

SURGERY

he physician caring for patients with type 1 diabetes must become famil-

iar with perioperative management. With excellent glucose manage-

ment, a person with diabetes can undergo surgery with little more than

normal risk.

GENERAL PRINCIPLES

The objectives of glycemic management during surgery are to maintain nor-

mal glucose levels and normal metabolism. Insulin resistance and glucogenesis

will increase during stress. For this reason, the customary basal insulin dosage

is the minimum requirement during the perioperative period. Additional insulin

also will be needed to prevent excessive hepatic glucose release and decreased

peripheral utilization while maintaining normal glucose levels and normal fluid

and electrolyte balance. Perioperative hyperglycemia will delay healing and

increase the risk of infection and ischemia. Although one large study suggested

that postoperative patients who are intubated and in the intensive care unit have

lower morbidity and mortality if they are treated to normoglycemia with an insu-

lin infusion, it is unclear whether this applies to patients with type 1 diabetes

or those who do not require ventilator support. Plasma glucose levels between

100 and 150 mg/dL (5.5 and 8.3 mmol/L) during and after the operation may

be a reasonable target range for patients who are less critically ill. An operative/

postoperative team guided by frequent point of care glucose monitoring, using

a simple and safe algorithm for intravenous insulin administration, can maintain

normal glucose levels and metabolism.

MAJOR SURGERY

Elective Surgery

The patient scheduled for elective surgery should be placed on intravenous

insulin and glucose several hours preoperatively and maintained at 100-150 mg/dL

(5.5 to 8.3 mmol/L). Evaluation of the metabolic state, lipid profile, renal func-

tion, and myocardial function must be completed before surgery. Once these

procedures are done, surgery can be performed at any time of the day based on

the urgency of the surgical condition.

Intravenous infusion of insulin rather than subcutaneous insulin administra-

tion is indicated during the perioperative period. Intravenous infusion allows

careful control of the amount and speed of insulin delivery and circumvents prob-

lems with subcutaneous absorption in the event of shock.

Emergency Surgery

In the event of emergency surgery requiring general anesthesia, there is usu-

ally sufficient time to optimally evaluate and stabilize the patient. In the event of

Special Situations

177

DKA in a patient who needs emergency surgery, e.g., trauma and ketoacidosis,

the condition can be treated concurrently with surgery.

MINOR SURGERY

Patients undergoing elective surgery with local anesthesia (e.g., dental work)

should eat only after surgery. The ideal management during these circumstances

is to withhold food, withhold short-acting insulin, and continue basal insulin as

insulin glargine or detemir or via insulin pump. If the person with type 1 diabetes

is being managed in some other manner, they should be switched to a basal-bolus

program before the elective procedure. Alternatively, the morning dose of NPH

can be decreased by one-third and supplemental regular insulin or rapid-acting

analogs can be used as needed.

CONCLUSION

Medical management of the patient with diabetes requiring surgery must

focus on provision of glucose and insulin in amounts to normalize blood glucose

levels during and after surgery. Intravenous insulin and glucose at a rate adjusted

for the individual’s insulin requirement titrated from frequent blood glucose

values can safely keep blood glucose levels between 100 and 150 mg/dL (5.5 and

8.3 mmol/L).

BIBLIOGRAPHY

ACE/ADA Task Force on Inpatient Diabetes: American College of Endocrinol-

ogy and American Diabetes Association Consensus Statement on Inpatient

Glycemic Control: A Call to Action. Diabetes Care 29:1955-1962, 2006

Pittas AG, Siegal RD, Lau J: Insulin therapy for critically ill hospitalized

patients: a meta-analysis of randomized controlled trials. Arch Intern Med

164:2005-2011, 2004

Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz

M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R: Intensive insulin

therapy in critically ill patients. N Engl J Med 345:1359-1367, 2001

Zerr KJ, Furnary AP, Grunkemeier GL, Bookin S, Kanhere V, Starr A: Glu-

cose control lowers the risk of wound infection in diabetics after open heart

operations. Ann Thorac Surg 63:356-361, 1997

178 Medical Management of Type 1 Diabetes

ISLET TRANSPLANTATION

ignificant progress in the field of islet transplantation has occurred over the

past years. In July 2000, a team from University of Alberta in Edmonton

reported success in achieving up to 14 months of insulin independence with

normalization of A1C and resolution of recurrent severe hypoglycemia in seven

type 1 diabetes patients by human islet allotransplantation from cadaver pancre-

ases. Their success was attributed to improved human islet isolation and purifica-

tion procedures, along with different immunosuppression regimens that avoid the

use of glucocorticoids and cyclosporine, which have in the past been shown toxic

to the islets. After their initial report, hundreds of other islet allotransplantations

into the portal vein of the liver have been done in designated research centers

around the world using variations of the Edmonton Protocol. Individual centers

reported good success; however, the 2006 results of a carefully conducted multi

center trial of the Edmonton Protocol were somewhat mixed: 44% of patients

achieved insulin independence and normalization of A1C at 1 year post-islet trans-

plantation, but the majority of patients required resumption of insulin therapy

in subsequent years of follow-up. More than one cadaver pancreas was used in

staged procedures in most patients, with some requiring islets from three or more

cadaver pancreases.

Success in human islet allotransplantation has not occurred without risks and

complications to the patients. The most significant complication has been hepatic

bleeding, with two reported cases of portal vein thrombosis. Other complications

include mouth ulcerations from sirolimus, transient rise in liver enzymes, the need

for statin therapy, renal dysfunction, severe neutropenia, and rare cases of pneu-

monitis, with one death from pneumonitis reported in a European center. No

cancers or infection with cytomegalovirus have been reported, but these remain

theoretical risks with longer-term immunosuppression.

As a result of these risks, islet allotransplantation is only recommended in a

research setting for patients where the benefits of improved metabolic control

with avoidance of severe hypoglycemia are greater than the risks of the islet allo-

transplantation procedure and the ongoing risks of chronic immunosuppression.

Most islet transplants to date have been done in patients with recurrent, refrac-

tory, severe hypoglycemia or marked glycemic instability. It is not known yet

whether such transplantation will reverse or stop microvascular complications,

because glucose intolerance persists.

Additional research is ongoing in multiple areas to improve the current clinical

results. These areas involve:

n improvement in islet yield from cadaver pancreases

n refinements to the protocol to improve engraphment

n long-term prevention and recurrence of autoimmunity

n development of safe immunomodulation strategies

n achievement of donor-specific immune tolerance

If success is achieved in these areas, the critical challenge will be to identify

sufficient and suitable sources of insulin-producing tissue to treat the large num-

ber of patients who could benefit from this therapy. For these reasons, research

Special Situations

179

on xenogeneic islets, embryonic and adult stem cells, islet regeneration and

proliferation, and engineering of insulin-producing cells must be continued. It

is important to identify the ideal source of insulin-producing tissue that will be

utilized on a large scale once the current impediments and limitations of immu-

nosuppression are resolved.

BIBLIOGRAPHY

Shapiro AMJ, Lakey JRT, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kne-

teman NM, Rajotte RV: Islet transplantation in seven patients with type 1

diabetes using a glucocorticoid-free immunosuppressive regimen. N Engl J

Med 343:230-238, 2000

Shapiro AM, Ricordi C, Hering BJ, Auchincloss H, Lindblad R, Robertson RP,

Secchi A, Brendel MD, Berney T, Brennan DC, Cagliero E, Alejandro R,

Ryan EA, DiMercurio B, Morel P, Polonsky KS, Reems JA, Bretzel RG,

Bertucci F, Froud T, Kandaswamy R, Sutherland DE, Eisenbarth G, Segal

M, Preiksaitis J, Korbutt GS, Barton FB, Viviano L, Seyfert-Margolis V,

Bluestone J, Lakey JR: International trial of the Edmonton Protocol for islet

transplantation. N Engl J Med 355:1318-1330, 2006

Highlights

Psychosocial Factors Affecting

Adherence, Quality of Life, and

Well-Being: Helping Patients Cope

Diabetes is a demanding chronic dis-

MAINTAINING ADHERENCE

ease. The diabetes management team

must understand the patient’s daily

n Over time or periodically, moti-

schedule, lifestyle, developmental

vation to maintain optimal diabetes

stage, social and financial supports, as

control may wane. Maintenance

well as preferences and values when

strategies include planning a lifestyle-

working collaboratively to make

based diabetes regimen, improving

diabetes management decisions and

patient/care provider communication,

establish treatment goals. Maintain-

addressing barriers, screening for

ing quality of life is as important an

depression, and employing research-

outcome as good glycemic control.

tested educational and behavioral

strategies.

PERIODS OF INCREASED

EMOTIONAL DISTRESS

DIABETES COMPLICATIONS

n Emotional distress can be high

n Psychosocial factors should be

at the time of diagnosis, when the

suspected in the case of extreme poor

honeymoon period is over, when

control and/or recurrent diabetic

planning pregnancy, and at the onset

ketoacidosis.

of complications. Psychological equi-

librium can generally be reestablished

n Repeat episodes of severe hypo-

with early identification of distress;

glycemia can have serious psycho

initiation of medical, psychological,

social consequences, which call for

and social supports; and monitoring

medical, educational, behavioral, and

of intervention effects. Initiation of

family intervention.

multidisciplinary intervention can

improve adaptation and adherence

n When chronic complications

and prevent deterioration in meta-

begin, feelings of anger and guilt are

bolic control.

common. Interventions that include

psychological counseling and adap-

n Monitoring of emotional status,

tive coping strategies can help resolve

quality of life, and well-being is an

these emotional reactions. Family

ongoing component of comprehen-

members should be included in the

sive diabetes care.

intervention whenever possible.

182

DEVELOPMENTAL

ADULTS

CONSIDERATIONS

IN CHILDREN

n Misunderstandings about diabetes

on the part of the patient or par-

n Although a diagnosis of diabetes

ent can interfere with young adult

during childhood can be a devastating

patients’ carrying out usual develop-

experience for parents and children,

mental tasks such as developing an

families are usually resilient and adapt

independent life from parents.

to the demands of the regimen within

the first year.

n Adults with diabetes must deal

with a disease and care regimen

n Because children and adolescents

that complicates their interpersonal

relationships and their attempts to

are growing, developing, acquiring

establish a family and career, and

new motor skills, cognitive abilities,

presents a financial burden as well.

and emotional maturity, the manage-

Thorough and anticipatory educa-

ment priorities and self-management

tion of paŧients, family members, and

issues change over time. However,

significant others can facilitate nor-

continued parental involvement is

malization of expectations.

necessary throughout childhood

and adolescence. Caution should be

exercised in forcing too much self-

THE ELDERLY

care too soon or abandoning parental

oversight during adolescence. Sharing

n Older adults with longstanding

diabetes care responsibilities pro-

diabetes can often benefit from

duces the best glycemic outcomes and

re-education regarding newer tech-

reduces individual burden.

nologies and care regimens.

n The demands of the diabetes reg

DEVELOPMENTAL

imen may be especially burdensome

CONSIDERATIONS

for the elderly, who face other diffi-

IN ADOLESCENTS

cult life events such as retirement, loss

of physical function, living on a fixed

n For adolescents, peer influences,

income, the death of a spouse and/or

together with family support and

friends, and their own mortality.

supervision, play an important role in

adherence and glycemic control.

n The goal of diabetes care is to

maximize physical and psychosocial

n Many aspects of the treatment

functioning while respecting the

regimen are at odds with adolescents’

patient’s autonomy and independence

normal drive for independence and

as much as possible. Availability and

peer acceptance. New technologies

maintenance of social support can be

have enabled adolescents to maintain

particularly difficult for the elderly,

a flexible lifestyle but at the cost of

who often find themselves dependent

increased monitoring and diabetes

on family and friends when physi-

care tasks.

cal capacities and financial resources

diminish.

183

EMOTIONAL AND

young women with a history of

BEHAVIORAL DISORDERS

unstable or poor metabolic control,

AND DIABETES

recurrent ketoacidosis, or recurrent

severe hypoglycemia, and in girls with

n Ongoing monitoring of the psy-

growth retardation, pubertal delay,

chological status of patients will help

and/or amenorrhea.

with detection of diabetes-related

distress and non-diabetes-related

psychopathology. It is important to

STRESS AND DIABETES

determine whether psychopathology

is diabetes related or due to other

n Results of studies investigating

causes.

the relationship between stress and

blood glucose control have been

n Whenever possible, it is recom-

inconclusive. The impact of stress on

mended that the care-provider team

glycemia seems to be highly individu-

include a mental health professional

alized.

familiar with diabetes and its care

regimen.

n It is important to establish a

patient’s stress reactivity to develop

n Depression and anxiety disorders

coping strategies to maintain good

have been found to occur frequently

glycemic control up to, during, and

in patients with diabetes. Some dis-

after stressful events.

orders, such as fear of hypoglycemia,

needle phobia, and fear of complica-

n Stress can indirectly affect blood

tions and premature death, are spe-

glucose control by undermining

cifically related to having diabetes.

adherence to the diabetes treatment

regimen.

n Eating disorders should be sus-

pected in individuals, especially

184

Psychosocial Factors Affecting

Adherence, Quality of Life, and

Well-Being: Helping Patients Cope

lthough type 1 diabetes taxes the patient’s psychosocial well-being, the

converse is also true: psychosocial factors can affect diabetes management.

The unrelenting demands, inconveniences, frustrations of treatment, and

possibilities of disability or death put tremendous emotional and financial strain

on patients with diabetes and their significant others. Patients must struggle con-

tinuously to achieve a balance between the demands of their everyday lives and

those of their diabetes regimen. To help patients cope successfully with diabetes

in their everyday lives, the diabetes management team must consider the patient’s

daily schedule, lifestyle, and developmental stage, social and financial supports,

and patient values and preferences when working collaboratively to make diabetes

management decisions and treatment goals. Maintaining quality of life is as impor-

tant an outcome as good glycemic control.

PERIODS OF INCREASED EMOTIONAL DISTRESS

Psychological and emotional distress is high at the time of diagnosis, after the

honeymoon period ends, and at the onset of complications (Table 5.1). At diag-

nosis, initial shock, denial, and anger often give way to mild depression and anxi-

ety. Studies of newly diagnosed children and their families have found, however,

that the initial reactions of both parents and children resolve rather quickly, and

psychological equilibrium is reestablished within the first year. More extreme or

long-lasting psychological reactions may indicate a need for referral to a mental

health professional for evaluation and treatment.

Ongoing monitoring of the emotional status of the patient is part of compre-

hensive diabetes care. Initiation of an intervention as soon as emotional distress is

identified may improve adaptation, prevent psychosocial maladjustment, improve

compliance, and prevent deterioration in metabolic control. All members of the

diabetes management team can be a great help during these periods by being

accessible and sensitive to the patient’s and family’s need for information, support,

and resources. When indicated, a referral to a mental health professional who

specializes in working with patients with diabetes is suggested.

The following are suggestions for intervention aimed at facilitating adjust-

ment and enhancing metabolic control.

n It is essential that the patient and his or her significant others are involved

in the initial and ongoing discussions and education regarding diabetes

care behaviors and regimens, lifestyle accommodations, sharing of diabetes

185

186 Medical Management of Type 1 Diabetes

Table 5.1 Factors Causing Emotional Distress

n Uncertainty about the outcome of the immediate situation

n Feelings of intense guilt and/or anger about the occurrence of diabetes, poor glycemic

control, and/or complications

n Feelings of incompetence and helplessness about the responsibility of managing the illness

n Fears about future complications and early death

n Loss of valued life goals and aspirations because of illness

n Anxiety about planning for an uncertain future

n Recognition of the necessity for a permanent change in living pattern as a result of diabetes

n Fear of loss of insurance coverage

Adapted from Hamburg SA, Inoff GE: Coping with predictable crises of diabetes. Diabetes Care

6:409-416, 1983.

care tasks, and the need to balance family needs with diabetes care tasks.

Both parents in the case of a child, the patient’s spouse, the adult chil-

dren in the case of an elderly patient, or any significant others should

be included. This is important given the wealth of research showing

significant associations between family and peer support and adherence,

problem-solving, and glycemic control. Research with families of children

who have diabetes has shown that sharing diabetes care tasks and respon-

sibilities reduces burdens and can improve glycemic control.

n A comprehensive approach to diabetes education and management can

be achieved if the roles of the diabetes management team are coordinated

and regular communication takes place between care providers. Led

by a physician or health professional who specializes in diabetes care,

involvement of a nurse educator, a dietitian, a social worker, and/or a psy-

chologist will ensure that the patient and family receive the educational,

dietary, and psychosocial support they need.

n Self-management education with newly diagnosed children and their

families in the months after diagnosis prevents deterioration in metabolic

control during the first 2 years after diagnosis of type 1 diabetes. Close

follow-up by the diabetes management team in the weeks after the ini-

tial education will increase, reinforce, and clarify diabetes knowledge.

Furthermore, emphasis on developing self-management strategies dur-

ing these weeks appears to enhance adaptation and metabolic control.

Self-management education includes reinforcement of accurate glucose

monitoring and recording and the use of these data to understand blood

glucose fluctuations and make appropriate insulin and behavioral treat-

ment changes. The goal is to help patients adopt a problem-solving

approach to diabetes self-management. See also Patient Self-Management

Education, page 37.

n Self-management education must be ongoing and accommodate the

developmental lifestyle and agreed-on treatment goals of the patient and/

or family members if the patient is a child, adolescent, or elderly person

who requires assistance with care.

Psychosocial Factors Affecting Adherence, Quality of Life, and Well-Being

187

n Goals of treatment, diabetes care regimen tasks, and expectations for gly-

cemic control should be negotiated with the patient and/or supervising

adult so that unrealistic goals do not cause burnout and feelings of failure.

MAINTAINING ADHERENCE

Expectations that an individual and family will make multiple and significant

behavior changes at one time may be unrealistic and unfeasible. Focus on “survival

skills” at the time of diagnosis (self-monitoring of blood glucose [SMBG], insu-

lin dosing, and monitoring and treatment of hypo- and hyperglycemia and keto-

sis) and clear communication about the expectation of working toward intensive

management of glucose control provide the foundation for success in diabetes self-

management. Explaining the importance of each of these survival skills and how

they will affect short- and long-term health is important. A step-by-step approach

to behavior change is often most successful, although highly motivated patients and

parents will attempt to implement health provider recommendations when they are

presented.

Failure to maintain self-care behaviors in diabetes management and resul-

tant poor metabolic control are frequently the result of the lack of attention to

maintenance issues. Caution is needed to monitor burnout and feelings of being

“controlled” by the disease.

Individualized Treatment Regimens

Regardless of age, a patient’s treatment regimen should be individually tai-

lored. Patients have been shown to follow complex treatment regimens when the

regimens meet the needs and requests of the patient and quality of life is main-

tained. Flexibility of lifestyle has become an important consideration in diabetes

care, and advances in monitoring technology, insulins, and delivery systems have

facilitated this aim. Holding a patient with diabetes to an inflexible diabetes care

routine might seem to providers to be an easier way to achieve good glycemic

control, but the negative impact on family and individual functioning should not

be underestimated and may actually undermine success.

The priorities and personality of the patient and his or her inherent organi-

zational proclivities should help shape the diabetes care regimen that is adopted.

For example, forcing a child or adult with attention-deficit hyperactivity disorder

to keep detailed glucose records may be an exercise in frustration for all involved.

Conversely, if such a patient prioritizes good glucose control, the diabetes care

regimen may provide structure by which the individual organizes his or her daily

routines. The adolescent, in particular, may be motivated to perform more fre-

quent monitoring, take additional insulin injections, and adhere to a specific

meal plan if it is perceived that he or she can participate in desired activities or

be granted special requests. Many adolescents and young adults are attracted to

and comfortable with technology, so tools such as software for organizing SMBG

reading may facilitate adherence and self-care. Conversely, some adolescents and

adults will attain better metabolic control with more adherence to a simplified

regimen than little or no adherence to a more complex or demanding regimen

such as being placed on the insulin pump or continuous glucose monitoring.

188 Medical Management of Type 1 Diabetes

Negotiations regarding treatment regimens should be viewed by the care

provider as an accommodation of the patient’s treatment within lifestyle realities

and shaped by the patient’s value system and preferences. Patients are people

who happen to have diabetes, and these people are the ones who must carry out

the vast majority of management tasks. This is a departure from the philosophy

of diabetes care in the past and may present difficulties for the care provider who

wishes to enforce a one-size-fits-all formula for good glycemic control. Adoption

of a patient-centered point of view not only is more likely to facilitate long-term

successful patient self-management, but also may help providers avoid burnout

and frustration as well.

DIABETES COMPLICATIONS

Short-Term Complications

Recurrent diabetic ketoacidosis can be the consequence of underdosing

or omission of insulin that occurs because of psychosocial problems, e.g., depres-

sion, psychiatric illness, financial stress, parental neglect, lack of family involvement,

chronic family conflict, weight concerns, or eating disorders. Psychosocial factors

should always be suspected in the case of recurrent ketoacidosis, especially after it has

been established that good glycemic control can be achieved under monitored condi-

tions. A mental health evaluation should be considered for these patients.

Severe Hypoglycemia

Most patients with well-controlled type 1 diabetes experience frequent hypo-

glycemia that is asymptomatic and several mildly symptomatic low blood glucose

reactions each month. In general, these symptomatic mild reactions, although

distracting and uncomfortable, do not pose a serious problem for the patient.

Severe hypoglycemia, however, defined as an episode in which patients are unable

to treat themselves, lose consciousness, and/or have seizures, can be frightening

and may have serious cognitive, neurological, and psychosocial consequences.

The patient may develop fear of hypoglycemia and decide to maintain blood glu-

cose values at unacceptably high levels. The family may also become overly fear-

ful, watchful, or angry, blaming the patient for the disturbing glycemic episodes.

Patients who experience severe hypoglycemia at work may jeopardize their job or

chances for advancement.

Many patients with longstanding, well-controlled type 1 diabetes fail to recog-

nize the early warning symptoms of hypoglycemia (hypoglycemia unawareness).

These patients are at risk for repeated episodes of severe hypoglycemia and atten-

dant medical and psychosocial consequences. Efforts should be made to prevent

these episodes through reeducation and adjustments in the diabetes regimen.

The health care provider should discuss the patient’s attitudes regarding hypo-

glycemia and help to establish safe blood glucose goals. Target blood glucose levels

may need to be raised to restore hypoglycemic awareness and the patient’s confi-

dence in recognition of symptoms. A program called Blood Glucose Awareness

Training (BGAT) successfully reduces the incidence of severe hypoglycemia.

The family or significant others should be trained to recognize early or subtle

Psychosocial Factors Affecting Adherence, Quality of Life, and Well-Being

189

hypoglycemic signs and provide adequate prevention and treatment measures,

including the administration of glucagon. If the family is angry and blames the

patient, the diabetes management team will need to help the family understand

the difficulty many patients have in recognizing and avoiding hypoglycemia. The

family should also understand that the patient frequently cannot control his or

her behavior during a severe low blood glucose reaction.

Long-Term Complications

Although most patients are aware of the possibility of long-term complica-

tions of diabetes, the detection of the first evidence of retinopathy, nephropathy,

or neuropathy can be a devastating event. When the onset of a severe complica-

tion occurs, the patient and family must cope with the grief associated with the

potential or actual loss of body function. Once again, the patient and family may

experience feelings of shock, denial, and anger. Feelings of anger at the health

care provider for “letting this happen” or guilt (“I should have taken better care

of myself”) are common. These feelings can be eased by emphasizing the posi-

tive steps that can still be taken to forestall or prevent serious problems. When

complications cause disability and restrictions in lifestyle, the treating physician

or health care provider may need to refer the patient to a rehabilitation program

that includes expert care or suggest counseling by an experienced mental health

professional who is familiar with the disease and its treatment. Support groups or

contact with people who have successfully adapted to complications can provide

useful information and role models and help patients maintain a hopeful outlook.

Care providers and patients may be hesitant to broach the issue of sexual

dysfunction—a common complication of diabetes in all adults, both men and

women. Though it is widely accepted that men with diabetes experience sexual

dysfunction, women (especially older women) with type 1 diabetes can experi-

ence a wide range of symptoms as well. It is critical to ask patients routinely

about sexual function in a straightforward manner. Patients may be more likely

to confide in the physician or another member of the diabetes management team

if they know that sexual problems are common in diabetes and that a variety of

treatment options are available. Along with issues of sexual functioning, issues of

reproductive health should be addressed with teens, young adults, and adults of

childbearing age. As modern diabetes care has enabled women with diabetes to

have healthy babies, misinformation about the inevitability of poor pregnancy

outcomes need to be counteracted. However, tight glycemic control is necessary

for a healthy pregnancy and baby. Patients with diabetes must plan pregnancies

and achieve excellent glycemic control before conception and maintain it through-

out pregnancy. This information should be incorporated into routine diabetes

care so that patients can make informed decisions regarding childbearing.

DEVELOPMENTAL CONSIDERATIONS IN CHILDREN

Although a diagnosis of diabetes during childhood is a devastating experience

for parents and children, families are usually resilient and adapt to the demands of

the regimen within the first year. Some of those demands, viewed from a devel-

opmental and family perspective, are outlined in Table 5.2.

190 Medical Management of Type 1 Diabetes

Table 5.2 Major Developmental Issues, Management Priorities, and

Family Issues in Type 1 Diabetes in Children and Adolescents

Developmental

Stages

Normal

Type 1 Diabetes

(approximate

Development

Management

Family Issues in Type 1

ages)

Tasks

Priorities

Diabetes Management

Infancy

• Developing a

• Preventing and

• Coping with stress

(0-12 months)

trusting

treating hypoglycemia

• Sharing the “burden of

relationship “bond-

• Avoiding extreme

care” to avoid parental

ing” with primary

fluctuations in blood glu-

burnout

caregiver

cose levels

Toddlers

• Developing a

• Preventing and

• Establishing a schedule

(13-36 months)

sense of mastery

treating hypoglycemia

• Managing the “picky eater”

and autonomy

• Avoiding extreme

• Setting limits and coping

fluctuations in blood

with toddler’s lack of

glucose levels due to

comprehension of regimen

irregular food intake

Preschoolers

• Developing

• Preventing and

• Reassuring child that

and early ele-

initiative in

treating hypoglycemia

diabetes is no one’s fault

mentary school

activities and

• Unpredictable appe-

• Educating other caregivers

(3-7 years)

confidence in self

tite and activity

about diabetes management

• Positive reinforce-

ment for cooperation

with regimen

• Trusting caregivers

with management

Older

• Developing skills

• Making diabetes

• Maintaining parental

elementary

in athletic,

regimen flexible to

involvement in insulin and

cognitive, artistic,

blood glucose monitoring

school

allow for participation in

social areas

tasks while allowing for inde-

(8-11 years)

school/peer activities

• Consolidating

pendent self-care for “special

• Child learning short-

self-esteem with

occasions”

and long-term benefits

respect to the

• Continue to educate school

of optimal control

peer group

and other caregivers

Early

• Managing body

• Managing increased

• Renegotiating parent and

adolescence

changes

insulin requirements

teen roles in management so

(12-15 years)

during puberty

acceptable to both

• Developing a

• Diabetes manage-

• Learning coping skills to

strong sense of

ment and blood glucose

gain ability to self-manage

self-identity

control become more

• Preventing and intervening

difficult

with diabetes-related family

• Weight and body

conflict

image concerns

• Monitoring for signs of

depression, eating disorders,

risk-taking behaviors

Later

• Establishing a

• Begin discussion of

•Supporting the transition to

adolescence

sense of identity

transition to a new dia-

independence

(16-19 years)

after high school

betes team

•Learning coping skills to

(location, social

• Integrating diabetes

gain ability to self-manage

issues, work,

into new lifestyle

•Monitoring for signs of

depression, eating disorders,

education)

risk-taking behaviors

Psychosocial Factors Affecting Adherence, Quality of Life, and Well-Being

191

Generally, children’s responsibilities for care should increase in tandem with

cognitive, motor, emotional, and psychological development. Children who share

responsibility for their diabetes care are generally more knowledgeable about

their diabetes and are in better metabolic control. When treating a school-age

child, the diabetes management team should be attuned to his or her cognitive

maturity and abilities with regard to accurately interpreting results of SMBG or

continuous glucose monitoring, calculating carbohydrate intake, and preparing

the correct amount of insulin with a pen, syringe, or pump. If cognitive abilities

are questioned, referral for testing by a psychologist familiar with the treatment

of diabetes should be considered.

Self-esteem is built through mastery of the developmental tasks of childhood

and the positive regard of significant others. Children feel good about themselves

when they succeed in tasks children their age are expected to master—school

work, sports, social relationships, etc. Having diabetes presents children with

opportunities to build self-esteem when they learn to perform diabetes-related

tasks. These may be as simple as setting up supplies for blood glucose tests or

as advanced as calculating the correct dose and giving their own injections or

wearing and/or operating an insulin pump. This is especially true if parents, the

diabetes management team, and others provide positive reinforcement for their

achievements. Conversely, expectations of independent functioning in diabetes

care tasks without the foundation of skill mastery, parental support and monitor-

ing, and adequate time-management skills or structure can predispose the child

to feelings of failure, low self-esteem, and feeling controlled by their illness. A

child’s comfort with self-care tasks should be monitored, because although a skill

may be mastered, the child’s desire to perform the task can change over time (e.g.,

during adolescence).

The Family

Diabetes affects every aspect of family life and affects all family members.

Research has shown that shared responsibility within the family is associated

with improved adherence and metabolic control. These results underscore the

importance of educating family members regarding the treatment of diabetes and

defining diabetes care tasks for each family member. Facilitating open discus-

sion of the problems encountered in day-to-day diabetes management will help

prevent blaming the child for poor diabetes control and enlist family support.

Siblings, who commonly feel neglected or left out because of the extra attention

given to the child with diabetes, may feel more involved if they are a part of the

family’s diabetes management effort, especially because they may be on the front

lines with regard to recognition of hypoglycemia and its treatment. Fathers may

be more likely to be involved if they, too, have clearly defined tasks. Full fam-

ily involvement may help prevent overinvolvement of the mother and unhealthy

dependence between the mother and the child with diabetes.

Diabetes, School, and Peers

Although school-aged children begin doing more diabetes management

tasks, it is important that parents and children continue to share diabetes care

192 Medical Management of Type 1 Diabetes

responsibilities. A child’s early independence in diabetes management can lead to

poor diabetes control. School entry can be a difficult experience for parents and

children. It is often more traumatic for the parent and child with diabetes, as they

must now depend on school nurses, teachers, and other school staff members (who

often are not knowledgeable about diabetes) to monitor the child’s well-being

and potentially handle situations that could be life-threatening. The student’s

health management team can help by providing diabetes literature and training

for school nurses, teachers and school staff, and by being advocates for the child

and family. Many school districts incorporate diabetes training for school nurses

into their overall training curriculum. Every effort should be made for the school

nurse and the diabetes management team to be familiar with each other and to

work collaboratively to manage the student/patient. There are programs that can

help bring nurses, teachers, administrators, other parents, and diabetes educators

together for training such as the American Diabetes Association’s “Safe at School”

program. Often there can be resistance with accommodating a child with diabetes

from school personnel due to fear of responsibility or misunderstanding of the

disease itself. Proper training can make everyone, families and faculty alike, feel

more at ease that a child with diabetes will be attending school and ensure a safe

and optimal learning environment for the child.

An important goal of diabetes management during childhood is to prevent

the diabetes regimen from disrupting the child’s school experience. Every effort

should be made to ensure the child’s safety at school and ability to participate

in all school activities. An individualized Diabetes Medical Management Plan,

developed by the student’s health care team (with input from the parent/guard-

ian), outlines what is required for diabetes management at school. Specific issues

outlined in the diabetes medical management plan are insulin administration;

signs, symptoms, and treatment of hypoglycemia and hyperglycemia; the timing

of meals; management of exercise; where and when SMBG occurs; and which

tasks need to be done by school personnel, which can be done independently, and

which require supervision. The school, mainly the school nurse, should deter-

mine how to execute the plan. Federal laws such as Section 504 of the Reha-

bilitation Act of 1973, the Americans with Disabilities Act, and the Individuals

with Disabilities Education Act prohibit schools from discriminating against chil-

dren with disabilities—including diabetes. Parents should work with their child’s

school to document required accommodations in a written plan developed under

applicable federal law such as a Section 504 Plan or an Individualized Education

Program (IEP). In addition, some states have laws that provide additional legal

protections to students with diabetes.

The student’s health care team should work with parents, teachers, and school

nurses to minimize absences and missed class time and school activities. Some

children may quickly learn to use their diabetes to avoid difficult school situa-

tions. Allowing children to check blood glucose levels and treat hypoglycemia at

their desks or in the classroom will help prevent missed classroom time. Children

who are frequently allowed to stay home for minor diabetes problems may fall

behind in school and lose motivation to return to school. Social stigmatization

can also occur because of being “sick” or “different.” Children and adolescents

with diabetes should be able to participate in all school-sponsored activities,

including field trips and sports.

Psychosocial Factors Affecting Adherence, Quality of Life, and Well-Being

193

During the elementary school years, peer relationships become increasingly

important. This means that the student’s health care team must work with par-

ents to ensure that children attend birthday parties and slumber parties, actively

participate in school and recreation league sports, and participate in other nor-

mal childhood activities. This does not mean relaxing treatment goals. Use of

basal-bolus insulin injection regimens or an insulin pump make adjusting to

calorie, activity, and timing changes in the child’s diabetes care routine feasible

and straightforward. Adequate preparation and planning can allow the child to

incorporate almost any usual childhood activity, including dosing of insulin for

excessive calorie consumption or consuming extra calories for high levels of

exercise.

DEVELOPMENTAL CONSIDERATIONS IN ADOLESCENTS

The adolescent years are known for difficulty with glycemic control, in part

because of innate insulin resistance associated with puberty, and in part because

of nonadherence to self-care regimens, and increased distress on the part of clini-

cians, parents, and the children themselves. Research has shown, however, that

these difficulties can be lessened and that strategies can be developed to maintain

glycemic control during this period of transition to early adulthood.

For the young child with diabetes, successful adherence to the treatment regi-

men depends largely on parental interest, management skills, and other resources.

For adolescents, peer influences, together with family support and supervision,

play an increasingly important role in adherence and glycemic control. Many

aspects of the treatment regimen are at odds with adolescents’ normal drive for

independence and peer acceptance. Adolescents may neglect monitoring, dietary

considerations, insulin administration, and even visits to the clinic to avoid draw-

ing attention to their illness or disturbing their daily activities. These actions can

have negative short-term consequences, such as feeling sluggish and unfocused

or developing ketoacidosis or severe hypoglycemia, as well as potentially nega-

tive long-term consequences in terms of future onset of chronic complications.

The diabetes management team can use various strategies to help the adolescent

patient and his or her family keep their diabetes control within acceptable limits.

Understand the Scope of the Challenge

Almost all adolescents display characteristic behaviors and attitudes that

reflect their drive for independence. Adolescents with diabetes are no exception.

They undergo the same developmental process but with the added burden of dia-

betes. Do not assume that major difficulties are inevitable. There is no evidence

that adolescents with diabetes suffer from serious psychological problems any

more frequently than their nondiabetic peers, though adults with diabetes show

a higher incidence of psychological distress than adults without diabetes. There

is evidence that interventions can be suggested that are acceptable to the ado-

lescent, parents, and health care providers that preserve glucose control and the

adolescent’s sense of autonomy. Use of the peer group and the diabetes manage-

ment team to support and monitor the health status and behaviors of adolescents

holds promise for affecting the decay in glycemic control often found during

194 Medical Management of Type 1 Diabetes

these years. Inclusion of the adolescent in devising a solution for nonadherence

and/or poor control is highly recommended.

Many hormonal changes occur at puberty, some of which can adversely affect

blood glucose levels. Puberty is associated with decreased sensitivity to insulin,

which may result in increased insulin requirements. Poor control may be due to

underinsulinization, lack of adherence, depression, or other psychopathologies

or poor understanding of required health care behavior on the part of the adoles-

cent. Do not assume nonadherence to care behaviors over a physiological reason

until good glycemic control has been achieved under supervised conditions uti-

lizing the current insulin and diabetes care regimen. Blaming the adolescent for

poor control can set the stage for further struggles with the adolescent and nega-

tively affect communication, which is essential to problem-solving. Empower the

adolescent as an agent of his or her own good health outcomes.

Family and Patient Factors

Because family routines overlap with the various aspects of the diabetes

treatment regimen (i.e., timing and content of meals, need for monitoring and

exercise), family factors and adherence to treatment are strongly interrelated.

Adherence to treatment is better among adolescents if their families are charac-

terized by lower levels of general and diabetes-related conflict, greater cohesive-

ness (i.e., family members interact more and are supportive of one another), and

clear assignments are made among family members for diabetes care tasks.

Effective clinical interventions with adolescents with diabetes and their fami-

lies should target (for change) negative family interactions, especially those that

focus on adherence with the care regimen. Whenever blood glucose values are

outside of a target range, rather than blaming the adolescent, it is important for

the family to problem-solve regarding the source of the poor glycemic control.

Parents may need guidance in setting realistic expectations for their teen’s self-

management behaviors and blood glucose levels. Parents face a difficult balanc-

ing act wherein they must respect their teen’s growing independence but remain

responsible for their child’s health and well-being. Negative family interactions

may have the inadvertent effect of undermining the teen’s attempts at indepen-

dence in diabetes care. Education and problem-solving intervention efforts with

adolescents should include parents, peers, and other acceptable support people,

including the diabetes care team, at least as external monitors of glycemic status.

Focus on the identification and development of coping strategies that decrease

diabetes-related conflicts and tensions in the family and facilitate mastery of dia-

betes care skills is recommended.

Diabetes Management Team Factors

In addition to acquiring an understanding of normal adolescent development,

members of the diabetes management team should enjoy working with adoles-

cents and show a genuine interest in them as individuals. Patient valuation of

their health care providers has been shown to be associated with better control.

It is important for the diabetes care provider to directly interact with and involve

the adolescent in his or her care, not just direct communication to parents.

Psychosocial Factors Affecting Adherence, Quality of Life, and Well-Being

195

Try to develop rapport. The diabetes management team should work toward

rapport with the teen. Clinicians should avoid being placed in a parental role

and make every effort to remain nonjudgmental and supportive in encouraging

mastery and success in diabetes care behavior. Recommendations that are viewed

by the adolescent as parental demands may be rejected. Clinicians are advised to

adopt a child advocacy stance when interacting with adolescents, only assuming

an authoritarian position when the child’s health is at risk or risk-taking behavior

is being demonstrated.

To avoid being viewed as parental figures, members of the diabetes man-

agement team should make it clear to both the parents and the adolescent that

they have responsibilities to each other. The clinician may agree or disagree with

either the parents or the adolescent about different aspects of diabetes care. An

attempt should be made to convince the adolescent and family that the clinician-

patient relationship is not one between clinician and child, but an evolving one

between clinician and young adult.

Be willing to compromise. Each member of the diabetes management team

must be willing to compromise on almost all aspects of diabetes care and must

clearly demonstrate respect for the adolescent’s views. If a clinician becomes frus-

trated and angry when the adolescent does not adhere to the regimen, it will be

difficult to retain the ability to influence the patient’s self-care. It is not neces-

sary to agree with the adolescent’s views, but the clinician should at least listen

to the patient and make an effort to accommodate the patient’s wishes whenever

possible.

Be consistent. An important factor known to affect adherence across all age-

groups is consistency in caregiving. The adolescent whose outpatient care is

provided by any one of several different diabetes management team members

with different management styles is not as likely to adhere to the regimen as the

patient seeing a diabetes management team with a consistent and predictable

management style. Often, an adolescent will form a bond with one team mem-

ber while professing to dislike another care provider. This may be face-saving

when the adolescent is nonadherent with care and gives health care providers the

opportunity to play “good cop-bad cop.” This situation is often found in nonad-

herent adults as well.

Monitoring

The adolescent should receive SMBG training (see Monitoring, page 88)

independent of his or her parents and demonstrate independent mastery. Adoles-

cents will be more likely to monitor if these results are used to make management

decisions and are perceived as increasing flexibility and safety while maintaining

metabolic control. It is important that when an adolescent becomes independent

in SMBG, a mechanism is set in place to communicate blood glucose results

either to parents and health care providers independent of parental oversight.

Parents and adolescents should review glucose results from SMBG using memory

in the meter or by downloading at set times during the week. Using multiple

meters can make this assessment more difficult. If the adolescent agrees to keep

a logbook, this can be reviewed, but SMBG results should be verified from the

196 Medical Management of Type 1 Diabetes

meter. The goal is to assess the frequency of monitoring, the degree of hypergly-

cemia and hypoglycemia, and to review patterns and trends. This review can take

place daily, weekly, or at some frequency in-between. A similar review should

take place at each clinic visit with the diabetes management team. When discuss-

ing the importance of monitoring to an adolescent, the diabetes management

team should emphasize that it is done primarily for the patient’s benefit and not

to placate or please the parents or clinician.

The same training procedures should occur if the adolescent is using con-

tinuous glucose monitoring so that they may gain independent mastery. Parents

and health care providers should assess the amount of time the teen is wearing

the sensor, how they are responding to glucose alarms, and if they are following

calibration instructions. It is important to emphasize that treatment decisions

must still be made from SMBG results, and that CGM is an adjunct and meant

to show trends and patterns. Studies have confirmed that use of CGM in ado-

lescents can be beneficial, and the more that sensors are worn, the better the

glycemic outcome.

Periodically, the adolescent patient may refuse to monitor at all. The heath

care team should not give up, but instead, renegotiate. If the adolescent is willing

to perform one test, another can be added at a future office visit. This step-by-

step approach often yields good results among adults as well as adolescents. Stress

to patients that they need to resume more frequent monitoring if they become ill

or are concerned about hypoglycemia.

Adolescents with diabetes can misrepresent glucose monitoring results. In the

past, it was possible to manipulate the glucose meter results by reusing an old strip

that had a “good” result, by diluting the blood specimen, or by using control solu-

tion. However, it has become increasingly difficult to falsify SMBG. Adolescents

may choose to tell their parents a false number as they are doing a blood test when

they are rushed, it is meal time, or as they are going out. If the parents suspect

that they were told a false number, they should ask to see the meter and check its

memory on the spot. Repeated misrepresentations should be suspected when the

mean glucose values recorded or reported are much lower than would be expected

from a very high glycated hemoglobin (A1C) level or when safe round numbers

appear to have been neatly recorded at the same time with the same pen.

When approaching the adolescent with an A1C out of target, insufficient

numbers of blood tests, or high values on SMBG, the diabetes management team

should not be judgmental. Accusations should not be made, but rather a problem-

solving approach will work best to engage the adolescent. Avoid discussions about

non-ideal glycemic control in an accusatory manner as this may cause the patient

to avoid the desired actions or change out of spite or rebellion.

This nonjudgmental approach may provide a good model for the parents,

who should be encouraged not to punish the adolescent for having high glucose

monitoring results and A1C. The diabetes management team should also remind

parents that other adolescents with diabetes (and even adults) have problems

adhering to the treatment regimen.

Parents often have great difficulty “letting go” of their role as primary man-

ager of their child’s diabetes. Parental worry for the child’s well-being is to be

expected, especially if parental responsibility for complications consequent to

poor control have been warned against since diagnosis. Parents and teens may

Psychosocial Factors Affecting Adherence, Quality of Life, and Well-Being

197

also be so used to interdependence in diabetes care that the child may view the

parent as “not caring anymore” if they appear to withdraw from active participa-

tion in diabetes management. Unless the parent is assured that diabetes care tasks

and reasonable glucose control are being maintained, they may be unable to let

their adolescent proceed to independence in care. The need for communication,

the method and frequency to be negotiated between parent and child, cannot be

underestimated. This developmental task is probably the most difficult of the

adolescent years, and diabetes exacerbates the dilemma. Keeping the issue in a

developmental framework can help patients, family members, and caregivers be

more tolerant of the uncertainties produced by transition in care responsibilities.

ADULTS

Marriage, family, employment, and finances are four major aspects of adult-

hood. Adults with diabetes must deal with a disease that often complicates their

interpersonal relationships and their attempts to establish a family and career and

presents a financial burden as well. Adults are often not prepared to include the

diabetes care team in the most intimate aspects of their lives, even though every

aspect of their lives is affected by having diabetes.

Development of intimate relationships can be burdened by the self-care regi-

men of the individual with diabetes or by short- and long-term complications

such as hypoglycemia or erectile dysfunction. Men in particular may be hesitant

to be seen in the patient role with their significant others. With the patient’s

agreement, the significant other can and should be incorporated into the diabetes

care routine with proper education and knowledge of the treatment regimen. It

is strongly advised that as a relationship becomes more important and central in

a patient’s life, the patient be encouraged to include the significant other in the

diabetes care visits. It is especially important that the new person learn about the

management of diabetes crises and methods of supporting adherence to the treat-

ment regimen without demeaning the patient or treating him or her as disabled.

Family planning counseling for couples planning a long-term commitment and

the possibility of children will provide crucial information as the couple decides

whether and/or when to have a child. Both partners should understand the risks

of pregnancy for the woman with diabetes and the need for optimal metabolic

control at the time of conception (see Pregnancy, page 161). Genetic counseling

should be included with education to dispel misunderstandings about the genetic

propensity to develop type 1 diabetes.

The diabetes management team should be able to provide psychosocial help

in many other ways during the adult years. They can offer education and counsel

when misunderstandings and conflicts arise in a marriage or other relationship

because of diabetes; refer patients to community, state, and federal programs to

help with financial problems; and educate and reassure children who worry about

their parents’ diabetes. Physicians can work with patients to match the regimen

to the realities of their job and consult with employers if problems with diabetes

management or employer misunderstanding of the disease and the legal rights of

the employee threaten a patient’s job security. The American Diabetes Association

provides resources for health care providers and patients dealing with discrimina-

tion issues in the workplace.

198 Medical Management of Type 1 Diabetes

THE ELDERLY

Because of increased survival rates, there is a growing number of older adults

with type 1 diabetes, in addition to the increasing number of older patients with

type 2 diabetes who require insulin. The elderly are often overlooked when new

technologies and medicines are offered. The assumption is that more complex

care is not feasible for this group of patients.

On the one hand, many older people are active and functional and may wish

to increase rather than decrease the intensity of their diabetes care. Retired people

may have more time and resources to devote to diabetes self-care skills. Because

of the availability of Medicare coverage, older people may have greater access to

health services and be able to afford to participate more actively in their care.

On the other hand, the demands of the diabetes regimen may be especially

burdensome for some elderly, especially those who face reduction in resources due

to retirement, loss of physical function and mobility, the death of a spouse and/or

friends, and their own mortality. Aging leads to declines in physical capacity due to

decreases in visual and auditory acuity, and diminished muscle mass, bone strength,

joint flexibility, and aerobic capacity. In addition to the physiological deterioration,

as many as 20% of the elderly may also have a diagnosable mental disorder, such

as anxiety, severe cognitive impairment, and depression. The elderly are prone to

hypoglycemia due to counterregulatory hormonal changes, the effects of concomi-

tant medications, and alterations of appetite and the physical capacity to eat. It may

be more difficult to keep physician appointments and purchase supplies because of

transportation problems and financial limitations. Before assumptions are made

about the needs or wishes of an elderly patient, a full current evaluation should

be conducted that includes social factors such as interpersonal support, financial

resources, and cognitive faculties. The diabetes management team should be aware

that errors in insulin administration and blood testing may be due to failing eye-

sight or poor coordination, forgetfulness, or lack of understanding of new treat-

ment modalities. It is essential for the diabetes management team to carefully assess

each older patient to identify and address these potential barriers to sound diabetes

care and, whenever possible, to identify a support person who is willing to monitor

the elder person’s health status and provide concrete assistance.

Inevitably, there are changes in social support as one ages. Those who have

helped in the past may no longer be able or available to do so. Social support is

important to the health and well-being of older adults, but its role will vary by

gender, race, marital status, and illness characteristics. It is important to deter-

mine the type of help needed to maintain respect for and autonomy of the older

person. The goal is to provide support while safeguarding the patient’s autonomy

and independence as much as possible. Home-care agencies and special pro-

grams, such as Meals-on-Wheels, are often helpful.

As emphasized for other age-groups, the relationship between the diabetes

management team and patient will influence patient adherence. Patients who are

satisfied with their team are more likely to adhere to their diabetes care plan.

However, older adults are less likely than other age-groups to express dissatisfac-

tion directly to the provider. Therefore, it is even more essential to encourage

open communication with this group by asking and responding to questions and

by taking time to show concern and discuss problems.

Psychosocial Factors Affecting Adherence, Quality of Life, and Well-Being

199

EMOTIONAL AND BEHAVIORAL DISORDERS AND DIABETES

It is important that care providers recognize emotional and behavioral disor-

ders in patients with diabetes and refer these patients for evaluation and counseling.

Some caregivers mistakenly view psychiatric symptoms, especially those of depres-

sion and anxiety, as expected or even normal in people coping with an illness as

serious and difficult to treat as diabetes. Unfortunately, when psychiatric symptoms

are seen as the norm, therapeutic intervention may not be recommended, and the

patient will continue to suffer psychological distress. This situation is especially

disturbing in light of the high prevalence of depression and anxiety disorders in

individuals with diabetes and the availability of effective treatment options.

Depression. Individuals with diabetes have higher rates of diagnoses of

depression than the general population of the US and of other developed coun-

tries. It is not known whether depression predisposes to diabetes, glucose toxic-

ity predisposes to depression, or some other central mechanism is operating that

affects both conditions. Depression in a patient with diabetes leads to an average

increase of 0.5-1.0% in the A1C level. Regardless, depression is still underdi-

agnosed, especially in teens and the elderly, and nonadherence due to depres-

sion is often underrecognized. Ongoing monitoring of patients’ mental status by

a multidisciplinary team will help with prompt diagnosis and treatment. When

depression is suspected, referral to a mental health provider is recommended.

Pharmacologic and behavioral treatments have both been shown to be effective

in treating depression. Incorporating the family and/or significant others into

psychological care is also recommended.

Anxiety disorders. Anxiety disorders such as needle phobia and fear of hypo-

glycemia may be a consequence of treatment with insulin. Other disorders such

as obsessive-compulsive disorder may be exacerbated by having diabetes. When

symptoms are identified that suggest these disorders, referral to specialists who

can initiate behavioral interventions while working with health care providers to

maintain diabetes care behaviors is imperative. The goal is to prevent deteriora-

tion in metabolic control while reducing symptoms that limit the patient’s ability

to carry out diabetes care tasks and that negatively affect quality of life. An anx-

iolytic medication in concert with behavioral intervention can also be utilized to

diminish symptoms. Once again, it is important not to mistake anxiety for willful

noncompliance, especially when the patient expresses distress in association with

specific diabetes care tasks (such as injections).

Fear of hypoglycemia may result in patients wishing to raise their glucose

levels to avoid the unpleasant feelings and loss of control associated with hypogly-

cemia. As mentioned earlier, BGAT has been shown to improve patients’ recog-

nition of their glycemic status and reduce the incidence of severe hypoglycemia.

Other forms of behavior therapy, used while temporarily raising glycemic targets,

can improve glycemic awareness in those who have lost feelings of hypoglycemia.

Increased blood glucose monitoring, use of continuous glucose monitoring, and

compensatory external cues can be enlisted to maintain glycemic status in those

with hypoglycemia unawareness.

It is important to treat the disorders in addition to looking for compensa-

tory management strategies (such as pump use, increased SMBG, or addition

200 Medical Management of Type 1 Diabetes

of continuous glucose monitoring). Parents in particular may respond to

their own anxiety by discussing “hurting” their child with insulin injections

of SMBG. This inadvertently fosters anxiety and solidifies a child’s fear. It is

particularly important to include parents in treatment when children express

anxiety over diabetes care behaviors, as the child/patient’s fears may mirror the

parent’s fears.

Eating disorders. Eating disorders are common in (but not exclusive to) ado-

lescent or young adult women with type 1 diabetes and are associated with poor

metabolic control, poor adherence to the diabetes regimen, and more severe

complications. Eating disorders are often related to the regain of and increasing

weight associated with successful treatment of diabetes with insulin, and they

may be exacerbated by the more intense focus on food that occurs in families of

children with diabetes. Diagnostic criteria for anorexia nervosa include weight

loss and maintenance of body weight 15% below norm, impaired body image,

intense fear of weight gain, and absence of menses. Diagnostic criteria for buli-

mia nervosa include recurrent episodes of binge eating, feelings of loss of control

over eating during binges, frequent self-induced vomiting and/or laxative use,

and overconcern with body image and weight.

Many young people with type 1 diabetes may have eating disturbances that

compromise their diabetes control yet do not meet stringent diagnostic criteria.

They may lose calories by intentional glycosuria rather than vomiting or laxative

use. This is accomplished by decreasing insulin doses or missing meal insulin

boluses. The seriousness of these subclinical cases should not be underestimated

because they can result in short- and long-term metabolic complications. Eat-

ing disorders, clinical and subclinical, should be suspected in young women with

persistently unstable or poor metabolic control, recurrent ketoacidosis resulting

from insulin omission to induce glycosuria and weight loss, or recurrent severe

hypoglycemia resulting from food restriction while continuing insulin, anxiety

or avoidance about being weighed, or binging with food or alcohol, and in girls

with growth retardation and pubertal delay. It is important that members of the

diabetes team routinely ask about eating behavior and insulin omission in a non-

threatening and nonjudgmental manner. These patients may require referral to

an experienced mental health professional for psychological evaluation and treat-

ment if an explanation for their problems is not found.

STRESS AND DIABETES

Although caregivers and patients have long observed a relationship between

stress and blood glucose levels, the results of numerous studies attempting to

define this relationship have yielded contradictory results. Some studies have

shown an association between stress and hyperglycemia, whereas others have

not. In some studies, this relationship has been idiosyncratic, with patients vary-

ing dramatically in their glucose response to the same or different stressors. The

only way to establish an individual’s stress reactivity is to monitor blood glucose

before, during, and after a stressful life event. Compensatory strategies should be

developed according to the patient’s individual response. Parents and teachers

need to be made aware of a child’s stress reactivity as it applies to schoolwork

Psychosocial Factors Affecting Adherence, Quality of Life, and Well-Being

201

and sports activities to plan a strategy to achieve glycemic targets during stressful

times in the child’s everyday life.

Stress can also have indirect effects on diabetes. Patients under stress may be

less able to follow their diabetes regimen, may give a low priority to their diabetes

care, or may respond to the stress by overeating or increasing their use of alco-

hol or illicit drugs. Care providers should explore possible explanations for poor

metabolic control. Some patients, while others may find support through family,

friends, religious community, or support groups, can learn to cope through stress

management counseling or relaxation training.

BIBLIOGRAPHY

Anderson RJ, Grigsby AB, Freeland KE, De Groot M, McGill JB, Clouse RE,

Lustman PJ: Anxiety and poor glycemic control: a meta-analytic review of

the literature. Int J Psychiatry Med 32:235-247, 2002

Brod M, Kongsø JH, Lessard S, Christensen TL: Psychological insulin resis-

tance: patient beliefs and implications for diabetes management. Quality of

Life Research 18:23-32, 2008

DCCT Research Group: Sexual dysfunction in women with type 1 diabetes:

long term findings from the DCCT/EDIC study cohort. Diabetes Care 32:

780-785, 2009

Kovacs J, Brent D, Steinberg TF, Paulauskas S, Reid J: Children’s self-report

of psychologic adjustment and coping strategies during first year of insulin-

dependent diabetes mellitus. Diabetes Care 9:472-479, 1986

Lustman PJ, Anderson RJ, Freedland KE, de Groot M, Carney RM, Clouse

RE: Depression and poor glycemic control: a meta-analytic review of the

literature. Diabetes Care 23:934-942, 2000

Lustman PJ, Penckofer SM, Clouse RE: Recent advances in understanding

depression in adults with diabetes. Current Diabetes Reports 7:114-122, 2007

Peyrot M, Rubin RR: Behavioral and psychosocial interventions in diabetes: a

conceptual review. Diabetes Care 30:2433-2440, 2007

Rodin G, Olmsted M, Rydall A, Maharaj S, Colton P, Jones J, Biancucci

L, Daneman D: Eating disorders in young women with type 1 diabetes

mellitus. J Psychosom Res 53:943-949, 2002

Schmitz N, Wang J, Lesage A, Malla A, Strychar I: Psychological distress and

short-term disability in people with diabetes: results from the Canadian Com-

munity Healthy Survey. Journal of Psychosomatic Research 65:165-172, 2008

Silverstein J, Klingensmith G, Copeland K, Plotnick L, Kaufman FR, Laffel L,

Deeb L, Grey M, Anderson B, Clark N: Care of children and adolescents

with type 1 diabetes mellitus: a statement of the American Diabetes Associa-

tion. Diabetes Care 28:186-212, 2005

Highlights

Complications

RETINOPATHY

n Lesions typical of nonproliferative

retinopathy, proliferative retinopathy,

n Significant retinopathy in patients

and macular edema are described

with type 1 diabetes rarely occurs

in Clinical Findings in Ðiabetic Reti-

before the fifth year of the disease.

nopathy (page 210).

n The clinician should assure that

n Treatment for diabetic retinopa-

patients receive their initial ophthal-

thy can be highly effective in preserv-

mologic examination within 5 years of

ing vision. Treatment modalities

onset of type 1 diabetes (for children

include

if >10 years of age and a diabetes

• scatter (panretinal)

duration of 3-5 years). Indications for

photocoagulation

more urgent ophthalmologic referral

• focal/grid laser photocoagulation

are described in Table 6.1.

• vitrectomy

n High-risk characteristics of pro-

liferative retinopathy greatly increase

n Medical therapies are discussed

the risk of blindness and include

under Treatment (page 214).

• new vessels on the optic disk

(NVD) involving greater than

NEPHROPATHY

~25% of the optic disk area

• any NVD with preretinal or

n Past epidemiologic studies sug-

vitreous hemorrhage

gested that up to 20-30% of patients

• new vessels elsewhere covering

with type 1 diabetes will eventually

an area ≥50% of the optic disk

develop kidney failure, although this

area (totaled for the entire retina)

rate may be decreasing with more

with preretinal or vitreous

effective screening and treatment.

hemorrhage

n Possible mechanisms by which

n When high-risk characteristics

diabetes damages the kidney are

are present, photocoagulation therapy

discussed in Pathogenesis. Elevated

should generally be performed

blood glucose, a genetic propensity,

promptly. An eye with severe non

elevated blood pressure, and abnor-

proliferative diabetic retinopathy,

mal glomerular hemodynamics have

or worse, should be considered for

been implicated.

photocoagulation.

205

n Renal function and albuminuria

(Charcot’s joints). All of these condi-

should be monitored annually in all

tions are avoidable with proper early

patients with type 1 diabetes after a

diagnosis of neuropathy and institu-

diabetes duration of 5 years or more.

tion of appropriate foot care.

n Patients with persistent micro-

n Treatment for diabetic distal sym-

albuminuria are at a higher risk for

metric polyneuropathy is symptom-

developing renal insufficiency and

atic, palliative, and supportive, with

may benefit from more intensive

primary emphasis on preventing the

glycemic control and ACE inhibitor

late complications.

therapy.

n Persistent and severely painful

n The management of more

neuropathy has been treated with

advanced diabetic nephropathy

various drugs, including standard

includes strict blood pressure control,

analgesics and drugs normally used

minimizing factors that are known to

to treat other conditions (anti-

accelerate the natural progression of

depressants, anti-convulsants).

renal disease or that may otherwise

Narcotics should be avoided.

jeopardize the kidney, and assisting

patients in responding to changing

n Although autonomic neuropathy

insulin needs (Tables 6.3 and 6.4).

produces diffuse subclinical dysfunc-

tion, autonomic symptoms are usually

n If kidney failure ensues, two

confined to one or two organ systems,

options are available: dialysis and kid-

producing the discrete autonomic

ney transplantation.

syndromes listed in Table 6.8.

n Erectile dysfunction in men with

NEUROPATHY

diabetes is usually neuropathic but

can also be psychogenic, endocrine,

n Diabetic neuropathy is classi-

vascular, or drug or stress related.

fied into a set of discrete clinical

syndromes, each with a characteris-

n Other dysfunctions related to

tic presentation and clinical course

autonomic neuropathy include dia-

(Table 6.5). The syndromes over-

betic cystopathy and hypoglycemia

lap clinically and frequently occur

unawareness.

simultaneously.

n Mononeuropathies comprise

n Distal symmetrical polyneu-

neural deficits corresponding to the

ropathy is the most common form of

distribution of single or multiple

diabetic neuropathy.

peripheral nerves and are usually

acute in onset and resolve spontane-

n Patients with chronic unrecog-

ously within weeks to months.

nized neuropathy may present with

late complications, e.g., foot ulcer-

n Screen for diabetic peripheral

ation, foreign objects embedded in

neuropathy (DPN) starting 5 years

the foot, unrecognized trauma to

after the diagnosis of type 1 diabetes

the extremities, or neuroarthropathy

and at least annually thereafter.

206

MACROVASCULAR DISEASE

neuropathy, and other disorders.

Glycation of tissue proteins may be

n Coronary heart disease, periph-

responsible for LJM, which is pain-

eral arterial disease, and cerebrovas-

less, can cause some disability, and is

cular disease are more common, tend

marked by a scleroderma-like stiffness

to occur at an earlier age, and are

of the skin and joints.

more extensive and severe in people

with diabetes.

n Subtle abnormalities of growth

and development affect 5-10% of

n Physicians should systematically

youngsters with type 1 diabetes and

assess patients for risk factors for

usually result from inadequate meta-

atherosclerotic cardiovascular disease,

bolic control.

question them about symptoms, and

be alert for signs of atherosclerosis.

n Signs of growth abnormalities

include a lag in height or weight or a

n A program for modifying risk fac-

falling away from the patient’s previ-

tors should be started if appropriate.

ously established growth curves.

n Guidelines for treatment of cere-

n Children most likely to be

brovascular disease, coronary heart

affected are those with the earliest

disease, and peripheral arterial disease

onset of diabetes and the worst gly-

appear in Symptoms and Signs of

cemic control. Boys are two to three

Atherosclerosis.

times more likely to be affected than

girls.

COMPLICATIONS IN

n To detect growth abnormalities,

CHILDREN

the physician should regularly plot

height and weight on standard growth

n Limited joint mobility (LJM),

charts. Other growth-impairing

which is not restricted to children,

conditions should be considered in

now occurs less often than in the past,

assessing growth abnormalities.

and is a potentially important clini-

cal marker for diabetes complications

such as retinopathy, nephropathy,

207

Complications

RETINOPATHY

iabetic retinopathy is one of the most common causes of blindness in the

US, the most common cause in those 20-74 years old, and is a major cause

of visual disability. Several surveys suggest that a person with diabetes has

a 5-10% chance of becoming legally blind and that this risk is greater in people

with type 1 than type 2 diabetes. Thirty-year data from the DCCT/EDIC and the

Pittsburgh Epidemiology of Diabetes Complications Experience (EDC) studies

encompassing the years 1983-2005 showed the differential risk by conventional

and intensive treatment groups for the DCCT/EDIC compared to the EDC

cohort. After 30 years of diabetes, the cumulative incidences of proliferative reti-

nopathy were 50% in the DCCT conventional treatment group, 47% in the EDC

cohort, and 21% in the DCCT intensive therapy group, and with fewer than 1%

legally blind.

Vision-threatening retinopathy virtually never appears in patients with type 1

diabetes in the first 3-5 years of diabetes or before puberty. Retinopathy detected

by fundus photography reaches a prevalence of 50% by the 10th year. By the 15th

year, up to 28% of patients have proliferative retinopathy, in which new blood

vessels develop from the retinal circulation, with a substantial risk of hemorrhage

and traction detachment of the retina. After 20 years’ duration of diabetes, nearly

all patients have some form of retinopathy. Earlier age at diagnosis, puberty, preg-

nancy, rapid intensification of blood glucose control, hypertension, hypercholes-

terolemia, anemia, use of tobacco, and presence of cataracts or cataract surgery

may exert an accelerating influence on the progression of retinopathy. Limited

data has suggested that vitamin D deficiency might be associated with an increased

prevalence of retinopathy in young people with type 1 diabetes. To reduce the risk

or slow the progression of retinopathy, optimization of glycemic control is impor-

tant, and to reduce the risk or slow the progression, it is critical to optimize blood

pressure control.

EYE EXAMINATION

Diabetic retinopathy appears primarily in the posterior retina and mid

periphery. Many but not all lesions may occur within an area viewable by the

nonophthalmologist with the monocular direct ophthalmoscope. However, this

examination is not an adequate substitute for an annual retinal examination by

an ophthalmologist or optometrist who is knowledgeable and experienced in the

detection of diabetic retinopathy. It has been demonstrated that non-eye care

professionals will miss a substantial amount of retinopathy, especially if pupils

are not dilated. Although the finding of retinopathy by indirect ophthalmoscopy

is well correlated with presence of disease and is important for prompt referral of

the patient, lack of observed retinopathy does not obviate the need for compre-

hensive ophthalmologic evaluation in patients with diabetes.

209

210 Medical Management of Type 1 Diabetes

CLINICAL FINDINGS IN DIABETIC RETINOPATHY

Mild to Moderate Nonproliferative Retinopathy

The earliest lesion visible through the ophthalmoscope is the microaneu-

rysm, a pouch-like dilation of a terminal capillary. Ophthalmoscopically, micro

aneurysms look like tiny red dots. Dot hemorrhages may be indistinguishable

from microaneurysms unless specialized techniques, such as fluorescein angi-

ography, are used, but blot hemorrhages may be recognized because they are

larger (Fig. 6.1). Hard exudates are another common feature of nonproliferative

retinopathy. Early nonproliferative retinopathy does not cause visual symptoms

unless it is associated with macular edema.

Severe to Very Severe Nonproliferative Retinopathy

Multiple extensive clustered blot hemorrhages throughout the retina sug-

gest progression to the severe nonproliferative stage. At this stage, substantial

portions of the capillary circulation may have become nonfunctional, and retinal

tissue is nonperfused. This nonperfusion may result in retinal hypoxia, which is

thought to stimulate new retinal blood vessel development.

Veins may appear dilated, tortuous, and irregular in caliber. Intraretinal

microvascular abnormalities are other signs of significant nonproliferative reti-

nopathy. These small loops of fine vessels usually extend from a major artery or

vein and probably represent early new-vessel formation within the retina. Fluffy

white lesions, commonly referred to as cottonwool spots, were formerly associ-

ated with this stage of retinopathy. Evidence suggests that these lesions, when

they appear alone, may be poor prognostic indicators.

Proliferative Retinopathy

Proliferative diabetic retinopathy involves the formation of new blood vessels,

extending from within the retinal substance onto the inner surface of the retina

or into the vitreous cavity. These vessels commonly occur on the optic nerve

head, where they are called new vessels on the disk (NVD) (Fig. 6.2). They may

also occur elsewhere in the retina, usually extending from major vessels, where

they are called new vessels elsewhere (NVE). New vessels are fragile and carry a

substantial risk of rupture with hemorrhage. The vessels also eventually undergo

fibrosis and contraction, capable of producing retinal detachment from the trac-

tional forces exerted.

Certain findings were defined as high-risk characteristics (HRC) by the national

Diabetic Retinopathy Study (DRS), a large-scale randomized controlled clinical trial

completed in 1981. The presence of HRC increases an eye’s risk of severe vision loss

(<25/200 on two consecutive visits at least 3 months apart) to 30-50% within 3-5 years

of detection if appropriate treatment is not provided. HRC include

n NVD greater than ~25% of the optic disk area

n any NVD with preretinal or vitreous hemorrhage

n NVE greater than or equal to 50% of the optic disk area (totaled for the

entire retina) with preretinal or vitreous hemorrhage

212 Medical Management of Type 1 Diabetes

When HRC are present, photocoagulation therapy (Fig. 6.3) is indicated to

preserve vision.

Diabetic Macular Edema

Macular edema involves thickening of the central portion of the retina. The

macula occupies an area of ~5 disk diameters just temporal to the optic nerve head

(Fig. 6.4). Visual acuity can be decreased in this condition, particularly when the

center of the macula (the fovea centralis) is involved. Macular edema is difficult to

diagnose with the direct ophthalmoscope because this instrument does not allow the

stereoscopic vision necessary to determine retinal thickening. However, the pres-

ence of hard lipid exudates—yellowish-white, often glistening, deposits of round or

irregular shape lying within the retina, usually in the macular region—strongly sug-

gests macular edema. This is particularly true if the exudates assume a ring-shape,

or circinate, configuration. The features of clinically significant macular edema are

n retinal thickening at or within 500 µm of the macular center

n hard exudates at or within 500 µm of the macular center with adjacent

retinal thickening

n retinal thickening >1 disk diameter in size any part of which is within

1 disk diameter of the macular center

When clinically significant macular edema is present, focal laser therapy

(Fig. 6.5) is indicated to preserve vision.

Glaucoma

Sometimes, in advanced (usually proliferative) diabetic retinopathy, new vessels

may also form on the surface of the iris and extend into the “angle” of the anterior

chamber of the eye, where the cornea and iris come together. Here, fibrous scar

tissue extending from the new vessels may block the outflow of aqueous humor

from the eye, causing a rise in intraocular pressure (neovascular glaucoma), severe

pain, and loss of vision. Angle-closure glaucoma, a major complication, is a rare

disorder in any age-group, especially before the age of 40 years.

EVALUATION

Patients with type 1 diabetes ≥10 years of age should have an annual detailed

ocular examination within 3-5 years after the onset of diabetes. In general, this

examination is not necessary before age 10 years. However, some evidence

suggests that the prepubertal duration of diabetes may be important in the devel-

opment of microvascular complications, so clinical judgment should be used

when applying this recommendation to individual patients. The screening exam-

ination should be done by an experienced ophthalmologist or optometrist and

should include

n determination of visual acuity of each eye

n refraction, especially if visual acuity is impaired

n gross external examination of the eyes

Complications

213

Figure 6.4

Diabetic

macular edema.

Figure 6.5 Focal

laser photoco-

agulation therapy for

clinically significant

macular edema.

Figures 6.1-6.5 provided by National Eye Institute, Institute of Health website: http://www

.nei.nih.gov/photo/keyword.asp?conditions=Diabetic. Accessed March 2012.

n evaluation of ocular motility

n examination of the eyes by slit-lamp biomicroscopy

n examination of the retina with monocular direct and binocular indirect

ophthalmoscopy after dilation of the pupils

n slit-lamp ophthalmoscopy to exclude macular edema

n in adult patients, measurement of intraocular pressures

Patients with any level of macular edema, severe nonproliferative retinopathy,

or any proliferative retinopathy require the prompt care of an ophthalmologist

who is knowledgeable and experienced in the management of diabetic retinopathy.

Further examinations may be carried out for specific indications. These include

214 Medical Management of Type 1 Diabetes

retinal photography, which is used to document lesions, and intravenous fluores-

cein angiography. During angiography, a fluorescent dye is injected into a vein,

and rapid-sequence photography of the retinal circulation is carried out. Both eyes

are typically evaluated at a single injection sequence.

Fluorescein angiography is useful clinically to plan photocoagulation treat-

ment for macular edema. Although it is more sensitive than ophthalmoscopy or

color photography for detecting very early lesions of retinopathy, the minute

lesions detected are rarely critical for making decisions regarding treatment.

Therefore, intravenous fluorescein angiography should not be used as a screen-

ing test in the annual ocular examination of patients with diabetes. Guidelines for

care and referral are described in Table 6.1.

TREATMENT

Clinicians should always refer patients for treatment of retinopathy to an

ophthalmologist, preferably one who is an expert in retinal disease (a retinal

specialist). If laser treatment (described below) has been recommended, the clini-

cian should ensure that the treatment has been implemented and that the patient

maintains the recommended follow-up.

Photocoagulation

Scatter (panretinal) photocoagulation. The principal method used to treat

diabetic retinopathy is by laser or light photocoagulation. For patients with

proliferative retinopathy and HRC, scatter photocoagulation with the laser is

standard therapy, based on DRS results and subsequent results from the Early

Treatment Diabetic Retinopathy Study (ETDRS), another large-scale random-

ized controlled clinical trial.

In this procedure, a series of 1,200-1,600 (or sometimes more) laser burns,

500 µm in diameter and spaced one-half burn diameter apart, are placed through-

out the midperipheral retina, avoiding the macular region (Fig. 6.3). The DRS

demonstrated that this procedure reduced the rate of progression to blindness by

50% in eyes with HRC over a 5-year follow-up. The ETDRS study suggested

that >95% of severe visual loss could be prevented if all patients received scatter

photocoagulation just as they exhibit HRC.

Many eyes with proliferative retinopathy but without HRC or with severe

nonproliferative retinopathy also will require scatter photocoagulation. The fac-

tors determining whether such patients should receive treatment include type

of diabetes, progression rate, contralateral eye status, systemic status, etc., and

should be discussed with the patient by the retinal specialist.

Patients undergoing scatter photocoagulation should have a clear under-

standing of what to expect from the procedure in terms of their vision. Often

prevention of severe visual loss is the goal, rather than improvement in vision.

The procedure itself may result in some loss of peripheral and/or night vision.

Focal/grid laser photocoagulation. Diabetic macular edema is treated by focal/

grid laser photocoagulation. With this technique, leaking microaneurysms and other

vascular abnormalities in the macular region, determined by fluorescein angiogra-

phy, are treated by direct application of small (50- to 100-µm) laser burns or laser

Complications

215

Table 6.1 Guidelines for Care

Routine Care by Physician

n Examine retina with direct ophthalmoscope annually and when indicated by symptoms

or previous findings

Referral to Eye Care Specialist

n Examine retinas through dilated pupils once a year (this need not be done before puberty

unless the patient has eye symptoms or other complications of diabetes)

Referral to Ophthalmologist

n At the beginning of pregnancy or if planning pregnancy within 12 months

n Moderate nonproliferative diabetic retinopathy, or worse

n Any level of macular edema (suggested by hard exudates within the macula)

n Immediate referral is mandatory (preferably to an ophthalmologist specializing in retinal

disease) if any of the following are present:

• NVD greater than ~25% of the optic disk area

•

any NVD with preretinal or vitreous hemorrhage

• NVE greater than or equal to 50% of the disk area with preretinal or vitreous

hemorrhage

n Reduced vision from any cause

n Immediate referral is strongly urged when the following are present:

• proliferative retinopathy without HRC

•

severe nonproliferative retinopathy, which includes

- dilated irregular veins

multiple dot and blot hemorrhages

- intraretinal microvascular abnormalities

burns placed in a grid-like pattern (Fig. 6.5). The ETDRS showed that this treatment

reduced the rate of visual loss from diabetic macular edema by 50% over a 3-year

follow-up.

Vitrectomy

Vitrectomy is a surgical procedure used primarily to 1) remove vitreous humor

filled with blood, 2) cut fibrous traction bands, 3) peel contractile fibrous mem-

branes from the inner retinal surface, and 4) repair some types of complex retinal

detachments. Vitrectomy is particularly effective in certain cases of advanced pro-

liferative diabetic retinopathy. Although it can restore useful vision to eyes that

would otherwise have severe visual impairment, vitrectomy is usually used only in

more diseased eyes, as there are significant potential surgical complications.

Medical Therapy

It is important to maintain normal blood pressure levels and near-normal

blood glucose levels in patients with retinopathy because diabetic retinopathy

progresses more rapidly in patients with uncontrolled hypertension and hyper-

glycemia than in those whose blood pressure and blood glucose are controlled.

216 Medical Management of Type 1 Diabetes

Control of systemic lipid levels is also important, as dyslipidemia is associated

with increased risk of hard exudates in the macula.

Therapies Under Evaluation

Other medical treatments for diabetic retinopathy have been evaluated.

n Aspirin (650 mg/day) was tested in the ETDRS because it inhibits platelet

aggregation. Platelet microthrombi have been proposed as a factor in the

cause of diabetic retinopathy. Aspirin was shown to be of no benefit or

risk for retinopathy in this study.

n Two experimental classes of drugs, both targeting pathways involved in the

pathogenesis of microvascular complications, may be useful in preventing

or reducing the progression of diabetic retinopathy: aldose reductase inhibi-

tors, inhibitors of protein kinase C and inhibitors of vascular endothelial

growth factors (VEGFs). Aldose reductase inhibitors have shown promise

in animal studies but have not yet shown good efficacy or safety in human

retinopathy trials. Although VEGF is implicated in the pathology of NV,

permeability and inflammation, it also has a beneficial role in ocular health.

Side effects of therapy with VEGF inhibitors are potentially significant and

studies continue to determine its role in diabetic eye disease.

CONCLUSION

Diabetic retinopathy is a common complication of long-term diabetes that

ranks as a leading cause of blindness and visual disability. Appropriate care

includes optimization of blood glucose, blood pressure, and serum lipid levels and

routine, life-long ophthalmic examinations. Although treatment strategies cannot

totally prevent or cure this complication, there is clear evidence that they can

substantially retard its progression if used appropriately and provided promptly

when indicated. Accordingly, careful optimization of glycemic control early and

persistently and other risk factors by the primary care physician, together with

annual screening by an eye care professional and referral of patients with signifi-

cant retinopathy to an ophthalmologist who is knowledgeable and experienced

in the management of diabetic retinopathy, is a standard of care for all patients

with diabetes.

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Complications

219

NEPHROPATHY

bout 40% of individuals starting dialysis in the US have diabetes, and

almost half of these have type 1 diabetes. In the past, epidemiological

studies suggested that 20-30% of patients affected with type 1 diabetes

would eventually develop kidney failure and require dialysis. More recent evi-

dence suggests that the frequency of nephropathy may be decreasing in the type 1

population with increased implementation of intensive glycemic control and wide

application of early screening and effective preventive measures. Thirty-year data

from the DCCT/EDIC and the Pittsburgh Epidemiology of Diabetes Complica-

tions Experience (EDC) studies encompassing the years 1983-2005 showed the

differential risk by conventional and intensive treatment groups for the DCCT/

EDIC compared to the EDC cohort. After 30 years of diabetes, the cumulative

incidences of nephropathy were 25% in the DCCT conventional treatment group,

17% in the EDC cohort, and 9% in the DCCT intensive therapy group and with

fewer than 1% requiring kidney replacement therapy.

CLINICAL SYNDROME

In its fully established form, diabetic nephropathy is a distinct clinical entity

characterized by proteinuria, hypertension, edema, and renal insufficiency; in its

most severe forms, nephrotic syndrome can be present. Diabetic nephropathy

occurs in type 1 diabetes patients with longstanding diabetes (usually over 10 years).

Histopathological Changes

Three classes of renal histopathological changes characterize diabetic

nephropathy: 1) glomerulosclerosis; 2) structural vascular changes, particularly

in the small arterioles; and 3) tubulointerstitial disease. Glomerular damage, e.g.,

mesangial expansion and basement membrane thickening, is the most charac-

teristic feature of diabetic nephropathy and most often takes the form of diffuse

scarring of entire glomeruli. The tubulointerstitial changes interfere with potas-

sium ion and hydrogen ion secretion and may be at least partly responsible for

the hyperkalemia and metabolic acidosis that accompany diabetic kidney disease.

NATURAL HISTORY

Shortly after diabetes is diagnosed, the glomerular filtration rate (GFR) and

renal blood flow are characteristically elevated, and there is typically a corre-

sponding increase in kidney weight and size. The increased GFR is related to the

degree of hyperglycemia, and the GFR and renal hypertrophy can be normalized

by improved glycemic control. The serum creatinine and urea nitrogen concen-

trations are slightly reduced when the renal hyperfiltration is present. Although

a slight increase in urine protein is common when a patient initially presents in

diabetic ketoacidosis, once glycemia is well regulated by insulin therapy, protein-

uria disappears and remains absent for many years.

Early in the course of diabetes, the renal histology is normal despite renal

hypertrophy. However, within 2-3 years, many kidneys demonstrate some

220 Medical Management of Type 1 Diabetes

histological evidence of mesangial expansion and basement membrane thick-

ening. Despite these histological changes, GFR and renal blood flow may

remain elevated, and proteinuria is not detectable. The earliest clinical evidence

of nephropathy is the appearance of low but abnormal levels (>30 mg/day or

30 µg/mg creatinine) of albumin in the urine. This subclinical range of increased

albumin excretion goes undetected with routine urine dipstick testing, but is

detectable with more sensitive techniques, and is sometimes referred to as micro-

albuminuria. Several factors can induce microalbuminuria, including poor glyce-

mic control, infection, and vigorous exercise. The presence of even microscopic

hematuria (or contamination by menstrual fluid) is sufficient to invalidate tests

for microalbuminuria. Albuminuria results vary widely from day to day, and

abnormal results should be confirmed by repeat testing.

Patients with confirmed microalbuminuria are referred to as having incipient

nephropathy and are at a higher risk for developing progressive kidney disease.

Without specific interventions, ~80% of subjects with type 1 diabetes who develop

sustained microalbuminuria have their urinary albumin excretion increase at a

rate of ~10-20%/year to the stage of overt nephropathy or clinical albuminuria

(>300 mg/24 h or ~300 µg/mg creatinine) over 10-15 years, with hypertension

also developing. In addition to being the earliest manifestation of nephropathy,

microalbuminuria is a marker of greatly increased cardiovascular risk for patients

with either type 1 or type 2 diabetes. Thus, the finding of microalbuminuria is an

indication for screening for possible vascular disease and aggressive intervention

to reduce all cardiovascular risk factors (e.g., lowering of LDL cholesterol, anti-

hypertensive therapy, smoking cessation, increased physical activity). In addition,

some preliminary evidence suggests that lowering cholesterol may also reduce the

level of proteinuria.

Once overt nephropathy occurs, without specific interventions, the GFR

gradually falls over several years at a rate that is highly variable from individual

to individual (2-20 ml/min/year). Kidney failure develops in 50% of patients

with type 1 diabetes with overt nephropathy within 10 years and in >75% by

20 years.

Although the GFR may still be elevated at the onset of proteinuria, it usu-

ally declines by ~50% within 3 years, and the serum creatinine and urea nitro-

gen concentrations become frankly elevated (>2.0 and >30 mg/dL, respectively).

Hypertension usually becomes manifest and become progressively more difficult

to treat. Within a mean of 2 years after the serum creatinine becomes elevated,

50% of the individuals will progress to kidney failure. The mean duration of

type 1 diabetes when ESRD develops is 23 years. With this, the uremic symp-

toms, e.g., drowsiness, lethargy, and nausea, appear and become progressively

more pronounced. Most patients receive treatment before reaching this stage,

and cardiovascular disease is now the most common cause of death in patients

with nephropathy.

Traditionally, it has been considered unusual in type 1 diabetes to observe

diabetic nephropathy in the absence of retinopathy, neuropathy, and hyperten-

sion. However, the correlation is close only in advanced kidney disease. As kid-

ney failure progresses, the incidence and severity of all three disorders increases

markedly, generally in parallel with renal status.

Complications

221

PATHOGENESIS

Considerable evidence suggests that diabetic nephropathy is related primarily

to the hyperglycemia induced by the diabetic state. First, renal changes are absent

initially in people biopsied around the time of onset of diabetes. Second, typical

changes of diabetic nephropathy occur in all types of diabetes. Third, diabetic

nephropathy appears in various animal models regardless of whether the diabetes

is induced or spontaneous, and the damage occurs in both original and trans-

planted kidneys. Fourth, in these diabetic animals, intensive insulin therapy or

islet cell transplantation completely prevents renal histopathologic changes and

may reverse early histopathologic abnormalities. Last, improved glucose control

can substantially delay the initial appearance of persistent microalbuminuria and

clinical grade albuminuria in type 1 diabetes.

Possible Mechanisms of Damage

The mechanisms by which diabetes damages the kidney are not completely

understood. Podocyte injury and depletion appear to play a role in the pathogen-

esis of diabetic kidney disease, and there is a strong correlation between podocyte

density, albuminuria, and renal function decline. Understanding of the regulatory

and signaling pathways involved in glomerular injury, including VEGF, Notch

signaling, and others, might lead to novel therapies for prevention and treatment

in the future. How these pathways might be triggered by elevated glucose per

se or by some metabolic event that occurs as a consequence of hyperglycemia remains

unknown.

A genetic propensity to diabetic nephropathy has been noted. Thus, it is pos-

sible that metabolic disturbances initiate the processes responsible for diabetic

nephropathy but that these processes operate on a genetic background that pre-

disposes to diabetic glomerulosclerosis. Some studies suggest the genetic predis-

position relates to an increased familial incidence of essential hypertension.

One explanation for renal damage may involve the typical increases in GFR

and renal blood flow that occur early in the course of diabetes. In animals, these

alterations in renal hemodynamics are associated with increased intraglomerular

pressures. Although it has not been possible to measure intraglomerular pressure

in humans, it has been suggested that glomerular hypertension is the ultimate

mediator of kidney damage in diabetic nephropathy. Measures aimed at reversing

the resulting hemodynamic changes have proved useful in slowing the progres-

sion of kidney disease in human diabetes.

TESTING FOR NEPHROPATHY

Because microalbuminuria rarely occurs with short duration of type 1 diabe-

tes or before puberty, screening in individuals with type 1 diabetes should begin

with puberty after disease duration of 5 years. Evidence suggests that the pre-

pubertal duration of diabetes may be important in the development of micro-

vascular complications, so clinical judgment should be used when applying this

recommendation to individual patients.

222 Medical Management of Type 1 Diabetes

Screening for microalbuminuria can be performed by three methods: 1) mea-

surement of the albumin-to-creatinine ratio in a random spot collection, 2) 24-h

collection, and 3) timed (e.g., 4-h or overnight) collection. The first method is the

easiest to carry out in an office setting and generally provides accurate information.

First-void or other morning collections are preferred because of the known diurnal

variation in albumin excretion, but if this timing cannot be used, uniformity of

timing for different collections in the same individual should be employed. Specific

assays are needed to detect microalbuminuria, because both standard dipsticks and

standard hospital laboratory assays for urinary protein are not sufficiently sensitive

to measure such levels. Microalbuminuria is defined as in Table 6.2.

In addition to annual assessment of urinary albumin, serum creatinine should

be measured at least annually and used to estimate GFR and to stage the level of

CKD, if present. GFR can be estimated using formulae such as the Cockroft-Gault

equation or a prediction formula using data from the Modification of Diet and Renal

Disease study. GFR calculators are available at http://www.nkdep.nih.gov. Many

clinical laboratories now report estimated GFR (eGFR) in addition to serum

creatinine. Although in the DCCT/EDIC albuminuria was a strong predictor

of eGFR loss and risk of developing sustained eGFR <60 ml/min/1.73 m², it is

estimated that albumin excretion rate alone would have missed 24% of cases of

sustained impaired eGFR. Therefore, it is recommended that serum creatinine be

measured annually in adults regardless of the degree of urine albumin excretion.

MANAGEMENT OF NEPHROPATHY

Incipient nephropathy: Confirmation of microalbuminuria should

trigger increased attention to improved glycemic control and the institution

of angiotensin converting enzyme (ACE) inhibitor therapy, both of which

have been shown to decrease the progression of nephropathy. The DCCT

demonstrated conclusively that intensive glycemic control reduces the

development and progression of early kidney disease. In the DCCT/EDIC

follow-up study at 22 years, there remained a 50% risk reduction in the

intensive therapy group. However, there is no evidence that tight glycemic

control through intensive insulin therapy can reverse or even slow the pro-

gression of severely advanced kidney disease.

ACE inhibitor therapy is discussed more fully in the section on hyperten-

sion, but is indicated for patients with macroalbuminuria as well as those with

Table 6.2 Definitions in Abnormalities of Albumin Excretion

24-h Collection Timed Collection

Spot Collection