Adverse effects include nausea, vomiting, and abdominal pain.

■ FURTHER READING

Apovian CM et al: Pharmacological management of obesity: An

Endocrine Society clinical practice guideline. J Clin Endocrinol

Metab 100:342, 2015.

Garvey WT et al: American Association of Clinical Endocrinologists

and American College of Endocrinology Comprehensive clinical

practice guidelines for medical care of patients with obesity. Endocr

Pract 22(suppl 3):1, 2016.

Jensen MD et al: 2013 AHA/ACC/TOS guideline for the management

of overweight and obesity in adults: A report of the American College

of Cardiology/American Heart Association Task Force on Practice

Guidelines and The Obesity Society. Circulation 129(suppl 2):S102,

2014.

Obesity Canada: Canadian Adult Obesity Clinical Guidelines

(CPGs). Available at https://obesitycanada.ca/guidelines/. Accessed

December 25, 2020.

3095 Diabetes Mellitus: Diagnosis, Classification, and Pathophysiology CHAPTER 403

TABLE 403-1 Etiologic Classification of Diabetes Mellitus

I. Type 1 diabetes (immune-mediated beta cell destruction, usually leading to

absolute insulin deficiency)

II. Type 2 diabetes (may range from predominantly insulin resistance with

relative insulin deficiency to a predominantly insulin secretory defect with

insulin resistance)

III. Specific types of diabetes (monogenic or MODY)

A. Genetic defects of beta cell development or function characterized by

mutations in:

1. Hepatocyte nuclear transcription factor (HNF) 4α

2. Glucokinase

3. HNF-1α

4. Insulin promoter factor-1, HNF-1β, NeuroD1, and other pancreatic islet

regulators/proteins such as KLF11, PAX4, BLK, GATA4, GATA6, SLC2A2

(GLUT2), RFX6, GLIS3

5. Insulin, leading to permanent neonatal diabetes

6. Subunits of ATP-sensitive potassium channel, leading to permanent

neonatal diabetes

7. Mitochondrial DNA

B. Transient neonatal diabetes

C. Diseases of the exocrine pancreas—pancreatitis, pancreatectomy,

neoplasia, cystic fibrosis, hemochromatosis, fibrocalculous

pancreatopathy, mutations in carboxyl ester lipase

D. Genetic defects in insulin action, including type A insulin resistance,

Leprechaunism, Rabson-Mendenhall syndrome, lipodystrophy syndromes

E. Endocrinopathies—acromegaly, Cushing’s syndrome, glucagonoma,

pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteronoma

F. Drug- or chemical-induced—glucocorticoids, calcineurin and mTOR

inhibitors (after organ transplantation), vacor (a rodenticide), pentamidine,

nicotinic acid, diazoxide, β-adrenergic agonists, thiazides, hydantoins,

asparaginase, α-interferon, protease inhibitors, antipsychotics (atypicals

and others), epinephrine

G. Infections—congenital rubella, cytomegalovirus, coxsackievirus

H. Uncommon forms of immune-mediated diabetes—”stiff-person”

syndrome, anti-insulin receptor antibodies

I. Other genetic syndromes sometimes associated with diabetes—Wolfram

syndrome, Down’s syndrome, Klinefelter’s syndrome, Turner’s syndrome,

Friedreich’s ataxia, Huntington’s chorea, Laurence-Moon-Biedl syndrome,

myotonic dystrophy, porphyria, Prader-Willi syndrome

IV. Gestational diabetes mellitus (GDM)

Abbreviation: MODY, maturity-onset diabetes of the young or monogenic diabetes;

see text.

Source: Data from American Diabetes Association. Standards of medical care in

diabetes–2014. Diabetes Care 37:S14, 2014.

(ESRD), nontraumatic lower-extremity amputations, and adult blindness. Persons with diabetes are at increased risk for cardiovascular

disease, which is the main cause of morbidity and mortality in this

population.

CLASSIFICATION

DM is classified on the basis of the pathogenic process leading to

hyperglycemia (Table 403-1). There are two broad categories of DM,

designated as either type 1 or type 2 DM. However, there is increasing

recognition of other forms of diabetes in which the molecular pathogenesis is better understood and may be associated with a single gene

defect. These alternative forms as well as other “atypical” forms may

share features of type 1 and/or type 2 DM. Type 1 DM develops as a

result of autoimmunity against the insulin-producing beta cells, resulting in insulin deficiency. Type 2 DM is a heterogeneous group of disorders characterized by variable degrees of insulin resistance, impaired

insulin secretion, and increased hepatic glucose production. Defects

in insulin action and/or secretion give rise to the common phenotype

of hyperglycemia in type 2 DM and have important therapeutic implications now that pharmacologic agents are available to target specific

metabolic derangements. Both type 1 and type 2 diabetes are preceded

by a period of progressive worsening of glucose homeostasis, followed

by the development of hyperglycemia that exceeds the threshold for

clinical diagnosis. In terms of type 2 diabetes, this phase is referred to

as prediabetes and is more specifically classified as impaired fasting

glucose (IFG) or impaired glucose tolerance (IGT) (Fig. 403-1).

Recently, three distinct stages of type 1 DM have been defined based on

the development of autoantibodies against pancreatic beta cell antigens

or the development of worsening dysglycemia (discussed below).

■ OTHER TYPES OF DM

Other etiologies of DM include specific genetic defects in insulin secretion or action, metabolic abnormalities that impair insulin secretion,

mitochondrial abnormalities, and a host of conditions that impair

glucose tolerance (Table 403-1). Maturity-onset diabetes of the young

(MODY) and monogenic diabetes are subtypes of DM characterized by

autosomal dominant inheritance, early onset of hyperglycemia (usually

<25 years; sometimes in neonatal period), and impaired insulin secretion (discussed below). Mutations in the insulin receptor cause a group

of rare disorders characterized by severe insulin resistance.

DM may also develop as a result of cystic fibrosis or chronic pancreatitis, in which the islets become damaged from a primary pathologic

process originating in the pancreatic exocrine tissue. Hormones that

antagonize insulin action can lead to DM. Hyperglycemia is often a

feature of endocrinopathies such as acromegaly and Cushing’s disease.

Viral infections have been implicated in pancreatic islet destruction

but are an extremely rare cause of DM. A form of acute onset of type 1

diabetes, termed fulminant diabetes, has been noted in Japan and may

be related to viral infection of the islets.

Normal

glucose

tolerance

<5.6 mmol/L

(100 mg/dL)

5.6–6.9 mmol/L

(100–125 mg/dL)

Symptoms of diabetes +

random blood glucose

concentration

≥11.1 mmol/L

(200 mg/dL)a

<7.8 mmol/L

(140 mg/dL)

7.8–11.0 mmol/L

(140–199 mg/dL)

≥11.1 mmol/L

(200 mg/dL)d

FPG

2-h PG

HbA1C

Impaired fasting

glucose or

impaired glucose

tolerance

Not

insulin

requiring

Insulin

required

for

control

Insulin

required

for

survival

Hyperglycemia

Pre-diabetes* Diabetes Mellitus

<5.6% 5.7–6.4% ≥6.5%c

≥7.0 mmol/L

(126 mg/dL)b

FIGURE 403-1 Spectrum of glucose homeostasis and diagnosis of diabetes mellitus

(DM). Glucose homeostasis is a spectrum from normal glucose tolerance (left

portion of figure) to diabetes (right portion of figure) including type 1 DM, type 2 DM,

specific types of diabetes, and gestational DM. The diagnostic criteria for diabetes

are shown in the lower right portion of the figure and include the hemoglobin A1c (HbA1c), the fasting plasma glucose (FPG), and the 2-h plasma glucose (PG) after

a glucose challenge. In most types of DM, the individual traverses from normal

glucose tolerance to impaired glucose tolerance to overt diabetes (these should be

viewed not as abrupt categories but as a spectrum). Changes in glucose tolerance

may be bidirectional in some types of diabetes. For example, individuals with type

2 DM may return to the impaired glucose tolerance category with weight loss; in

gestational DM, diabetes may revert to impaired glucose tolerance or normal

glucose tolerance after delivery. a

Random is defined as without regard to time since

the last meal. b

Fasting is defined as no caloric intake for at least 8 h. C

Hemoglobin A1c

test should be performed in a laboratory using a method approved by the National

Glycohemoglobin Standardization Program and correlated to the reference assay

of the Diabetes Control and Complications Trial. Point-of-care hemoglobin A1c

should not be used for diagnostic purposes. d

The test should be performed using

a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in

water, not recommended for routine clinical use. Assessment of 1-h glucose may

be helpful in diabetes risk prediction in individuals with cystic fibrosis or other forms

of pancreatic disease. In the absence of unequivocal hyperglycemia and acute

metabolic decompensation, the blood glucose criteria should be confirmed by repeat

testing on a different day. These values do not apply to the diagnosis of gestational

DM. *

Some use the term increased risk for diabetes or intermediate hyperglycemia

(World Health Organization) rather than prediabetes. (Data from American Diabetes

Association. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care

in Diabetes-2021. Diabetes Care 44:S15, 2021.)

3096 PART 12 Endocrinology and Metabolism

There is considerable geographic variation in the incidence of both

type 1 and type 2 DM. Currently, Scandinavia, followed by Sardina and

Portugal, have the highest incidence of type 1 DM; the lowest incidence

is in the Pacific Rim where it is twenty- to thirtyfold lower. Northern

Europe and the United States have an intermediate rate. Much of the

increased risk of type 1 DM is believed to reflect the frequency of highrisk human leukocyte antigen (HLA) alleles among ethnic groups in

different geographic locations. However, now populations less enriched

with these classic high-risk HLA alleles are experiencing more rapid

increases in type 1 DM incidence, suggesting an influence of environmental factors.

The prevalence of type 2 DM and its harbinger, IGT, is highest in

certain Pacific islands and the Middle East and intermediate in countries such as India and the United States. This variability is likely due

to genetic, behavioral, and environmental factors. DM prevalence also

varies among different ethnic populations within a given country, with

indigenous populations usually having a greater incidence of diabetes

than the general population of the country. For example, the CDC estimated that the age-adjusted prevalence of DM in the United States (age

>20 years; 2017–2018) was 7.5% in non-Hispanic whites, 9.2% in Asian

Americans, 12.5% in Hispanics, and 11.7% in non-Hispanic blacks, but

it exceeds 14% in American-Indian and Alaskan native populations.

The onset of type 2 DM occurs, on average, at an earlier age in ethnic

groups other than non-Hispanic whites. In Asia, the prevalence of

diabetes is increasing rapidly, with an onset at a lower body mass index

(BMI) and younger age, greater visceral adiposity, and reduced insulin

secretory capacity.

Diabetes is a major cause of mortality. In recent years, diabetes has

been listed as the seventh leading cause of death in the United States,

but several studies indicate that diabetes-related deaths are likely

underreported. In 2019, data from the IDF suggest that diabetes was

responsible for nearly 4.2 million deaths worldwide, accounting for

11.3% of global all-cause mortality in adults aged 20–79 years. Diabetes

also has important economic implications. In 2019, it was estimated

that $760 billion of health care expenditures worldwide were spent

on diabetes (a range of 8–19% of total expenditures across regions).

Up to 75% of individuals with diabetes live in low- or middle-income

countries.

DIAGNOSIS

Glucose tolerance is classified into three broad categories: normal glucose homeostasis, impaired glucose homeostasis, or DM (Fig. 403-1).

Glucose tolerance can be assessed using the fasting plasma glucose

(FPG), the response to oral glucose challenge, or the hemoglobin

A1c (HbA1c). An FPG <5.6 mmol/L (100 mg/dL), a plasma glucose

<7.9 mmol/L (140 mg/dL) following an oral glucose challenge, and

an HbA1c <5.7% are considered to define normal glucose tolerance.

The International Expert Committee with members appointed by

■ GESTATIONAL DM

Glucose intolerance developing during the second or third trimester of

pregnancy is classified as gestational diabetes mellitus (GDM). Insulin

resistance is related to the metabolic changes of pregnancy, during

which the increased insulin demands may lead to IGT or diabetes.

The American Diabetes Association (ADA) recommends that diabetes

diagnosed within the first trimester be classified as preexisting pregestational diabetes rather than GDM. In 2019, the International Diabetes

Federation (IDF) estimated that 16% of pregnancies worldwide were

affected by either GDM or preexisting DM. Most women with GDM

revert to normal glucose tolerance postpartum but have a substantial

risk (35–60%) of developing DM in the next 10–20 years. In addition,

children born to a mother with GDM also have an increased risk of

developing metabolic syndrome and type 2 DM later in life. Currently,

the ADA recommends that women with a history of GDM undergo

lifelong screening for the development of diabetes or prediabetes at

least every 3 years.

■ ATYPICAL DIABETES

It is increasingly recognized that some forms of diabetes have features

of both type 1 and type 2 diabetes. These are distinct from monogenic

forms (MODY) as they have not been linked to single gene defects.

The development of a type 2 diabetes phenotype before puberty and

a type 2 diabetes phenotype in very lean individuals are examples of

atypical diabetes. An additional example is ketosis-prone diabetes,

where individuals present with ketoacidosis, but do not require longterm exogenous insulin therapy. Many of these individuals are African

American or Asian in heritage. Mechanisms underlying atypical forms

of diabetes are being actively studied.

EPIDEMIOLOGY AND GLOBAL

CONSIDERATIONS

The worldwide prevalence of DM has risen dramatically over the past

two decades, from an estimated 30 million cases in 1985 to 463 million in

2019 (Fig. 403-2). Based on current trends, the IDF projects that 642 million individuals will have diabetes by the year 2040 (see http://www.idf.

org/). Although the prevalence of both type 1 and type 2 DM is increasing

worldwide, the prevalence of type 2 DM is rising much more rapidly,

presumably because of dietary changes and increasing obesity, reduced

activity levels as countries become more industrialized, and aging of

the population. The incidence of type 1 diabetes has been increasing

at a rate of 3% per year worldwide, with clear geographic differences.

The cause for this increase is not well understood, but type 1 DM is

increasingly being diagnosed at younger ages. In 2019, the prevalence of

diabetes in individuals aged 20–79 years worldwide was 9.3%, ranging

from 4.7–12.2%. The countries with the greatest number of individuals

with diabetes in 2019 were China (116.4 million), India (77 million), the

United States (31 million), Pakistan (19.4 million), Brazil (16.8 million),

and Mexico (12.8 million). In the most

recent estimate for the United States

(2020), the Centers for Disease Control

and Prevention (CDC) estimated that

10.5% of the population had diabetes.

Diabetes affected 13% of all U.S. adults,

and as many as 34% or 88 million U.S.

adults had prediabetes. Approximately

21.4% of U.S. adults with diabetes in the

United States were undiagnosed; globally,

it is estimated that as many as 50% of

individuals with diabetes may be undiagnosed. The prevalence of DM increases

with age. The prevalence of DM in the

United States was estimated to be 0.25%

in individuals age <20 years, 4.2% in

persons aged 18–44 years, and 17.5% in

persons 45–64 years old. In individuals

aged >65 years, the prevalence of DM

was 26.8%. Similar age-related trends

have been observed worldwide.

163 M

88 M

59 M

55 M

48 M

32 M

19 M

FIGURE 403-2 Worldwide prevalence of diabetes mellitus. Global estimate is 463 million individuals with diabetes in

2019. Regional estimates of the number of individuals with diabetes (20–79 years of age) are shown (2019). (Data from

the IDF Diabetes Atlas, 9th ed. The International Diabetes Federation; 2019.)

3097 Diabetes Mellitus: Diagnosis, Classification, and Pathophysiology CHAPTER 403

TABLE 403-2 Criteria for Screening for Type 2 Diabetes Mellitus

in Adults

1. Consider testing in overweight or obese (BMI ≥25 kg/m2

, ≥23 kg/m2

 in Asian

Americans, or other ethnically relevant definition who have these risk factors:

• Family history of diabetes (i.e., parent or sibling with type 2 diabetes)

• Race/ethnicity (e.g., African American, Latino, Native American, Asian

American, Pacific Islander)

• Hypertension (blood pressure ≥140/90 mmHg)

• HDL cholesterol level <35 mg/dL (0.90 mmol/L) and/or a triglyceride level

>250 mg/dL (2.82 mmol/L)

• Polycystic ovary syndrome or acanthosis nigricans

• History of cardiovascular disease

• Physical inactivity

• Other condition associated with insulin resistance (severe obesity,

acanthosis nigricans)

2. Individuals with previously identified IFG, IGT, or a hemoglobin A1c of 5.7–6.4%

should be screened annually.

3. Women who had GDM should be screened at least every 3 years.

4. For other individuals, initiate testing at 45 years of age and repeat every

3 years.

5. Individuals with HIV

Abbreviations: BMI, body mass index; GDM, gestational diabetes mellitus; HDL,

high-density lipoprotein; IFG, impaired fasting glucose; IGT, impaired glucose

tolerance; HIV, human immunodeficiency virus.

Source: Adapted with permission from American Diabetes Association.

2. Classification and diagnosis of diabetes: Standards of medical care in

diabetes-2021. Diabetes Care 44:S15, 2021.

the ADA, the European Association for the Study of Diabetes, and the

IDF have issued diagnostic criteria for DM (Table 403-2) based on the

following premises: (1) the FPG, the response to an oral glucose challenge (oral glucose tolerance test [OGTT]), and HbA1c differ among

individuals, and (2) DM is defined as the level of glycemia at which

diabetes-specific complications occur rather than deviation from a

population-based mean. For example, the prevalence of retinopathy in

Native Americans (Pima Indian population) begins to increase at an

FPG >6.4 mmol/L (116 mg/dL) (Fig. 403-3).

Abnormal glucose homeostasis can be diagnosed by three distinct

criteria (Fig. 403-1). First, impaired fasting glucose (IFG) is defined as

a fasting plasma glucose (FPG) value of 5.6–6.9 mmol/L (100–125 mg/

dL). Second, impaired glucose tolerance (IGT) is defined as a plasma

glucose level of 7.8–11 mmol/L (140–199 mg/dL) following an oral

glucose challenge. Third, an HbA1c of 5.7–6.4% reflects dysglycemia

by all mechanisms. While an HbA1c of 5.7–6.4%, IFG, and IGT do

not identify the same individuals (i.e., different biologic mechanisms

involved), individuals in all three groups are at greater risk of progressing to type 2 DM, have an increased risk of cardiovascular disease, and

should be counseled about ways to decrease these risks (see below).

Some use the terms prediabetes, increased risk of diabetes, or intermediate hyperglycemia (World Health Organization) and slightly different

metrics for this category.

It is important to recognize that these values for the FPG, the

glucose following an oral glucose challenge, and HbA1c are continuous rather than discrete variables; risk for comorbidities increases

continuously rather than discretely by diagnostic category. A FPG

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

2 h after an oral glucose challenge, or an HbA1c ≥6.5% meets the criteria for the diagnosis of DM (Fig. 403-1). A random plasma glucose

concentration ≥11.1 mmol/L (200 mg/dL) accompanied by classic

symptoms of DM (polyuria, polydipsia, weight loss) is also sufficient

for the diagnosis of DM. The current criteria for the diagnosis of DM

emphasize the HbA1c and the FPG as the most reliable and convenient

tests for identifying DM in asymptomatic individuals. However, some

individuals may meet criteria for one test but not the other. Also, it is

important to note that race and ethnicity may impact the reliability of

HbA1c levels. For example, African Americans have a higher HbA1c

value compared to non-Hispanic whites with a similar level of glycemia. An OGTT, although a valid means for diagnosing DM, is not often

used in routine clinical care with the exception of pregnancy care and

screening for gestational diabetes.

The diagnosis of DM has profound implications for an individual

from both a medical and a financial standpoint. Thus, abnormalities

on screening tests for diabetes should be repeated before making a

definitive diagnosis of DM, unless acute metabolic derangements or a

markedly elevated plasma glucose are present. These criteria also allow

for the diagnosis of DM to be withdrawn in situations when the glucose

intolerance reverts to normal.

■ SCREENING

Widespread use of the FPG or the HbA1c as a screening test for type 2

DM is recommended because (1) a large number of individuals who

meet the current criteria for DM are asymptomatic and unaware that

they have the disorder, (2) epidemiologic studies suggest that type

2 DM may be present for up to a decade before diagnosis, (3) some

individuals with type 2 DM have one or more diabetes-specific complications at the time of their diagnosis, (4) treatment of type 2 DM may

favorably alter the natural history of DM, and (5) diagnosis of prediabetes should spur efforts for diabetes prevention. The ADA recommends

screening all individuals aged >45 years every 3 years and screening

individuals at an earlier age if they are overweight (BMI >25 kg/m2

 or

ethnically relevant definition for overweight) and have one additional

risk factor for diabetes. Although a number of immunologic markers

for type 1 DM are becoming available (discussed below), their routine

use outside a clinical trial is discouraged, pending the identification

of clinically beneficial interventions for individuals at high risk for

developing type 1 DM.

REGULATION OF GLUCOSE HOMEOSTASIS

■ OVERALL REGULATION OF

GLUCOSE HOMEOSTASIS

Glucose homeostasis reflects a balance between energy intake from

ingested food, hepatic glucose production (gluconeogenesis), and

peripheral tissue glucose uptake and utilization. Insulin is the most

important regulator of this metabolic equilibrium, but neural input,

metabolic signals, and other hormones (e.g., glucagon) result in

integrated control of glucose supply and utilization (Fig. 403-4). The

organs that regulate glucose and lipids communicate by neural and

humoral mechanisms with fat and muscle producing adipokines,

myokines, and metabolites that influence liver function. In the fasting

15

A FPG

2-h PG

A1C

10

5

0

FPG (mg/dL)

2-h PG (mg/dL)

HbA1c (%)

70 89 93 97 100 105 109 116 136 226

38 94 106 116 126 138 156 185 244 364

3.4 4.8 5.0 5.2 5.3 5.5 5.7 6.0 6.7 9.5

Retinopathy (%)

FIGURE 403-3 Relationship of diabetes-specific complication and glucose

tolerance. This figure shows the incidence of retinopathy in Pima Indians as

a function of the fasting plasma glucose (FPG), the 2-h plasma glucose after a

75-g oral glucose challenge (2-h PG), or the hemoglobin A1c (HbA1c). Note that

the incidence of retinopathy greatly increases at a FPG >116 mg/dL, a 2-h PG of

185 mg/dL, or an HbA1c >6.5%. (Blood glucose values are shown in mg/dL; to convert

to mmol/L, divide value by 18.) (Modified with permission from 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:S5, 2003.)

3098 PART 12 Endocrinology and Metabolism

state, low insulin levels, together with modest increases in glucagon,

increase glucose production by promoting hepatic gluconeogenesis

and glycogen breakdown (glycogenolysis). In parallel, glucose uptake

in insulin-sensitive tissues (skeletal muscle and fat) is reduced, and

there is increased mobilization of gluconeogenic precursors such as

amino acids and free fatty acids (lipolysis). Under normal conditions

alpha cells increase glucagon secretion only when blood glucose or

insulin levels are low or during exercise, but it is increased in fasting

and postprandially in DM and stimulates excess glycogenolysis and

gluconeogenesis by the liver and to a small degree by the renal medulla

(Chap. 406). Conversely, in healthy people, the postprandial glucose

load elicits a rise in insulin and fall in glucagon, leading to optimized

glucose disposal. Insulin, an anabolic hormone, promotes the storage

of carbohydrate and fat and protein synthesis. The major portion of

postprandial glucose is utilized by skeletal muscle, an effect of insulinstimulated glucose uptake. Other tissues, most notably the brain, utilize

glucose in an insulin-independent fashion. Factors secreted by skeletal

myocytes, adipocytes (e.g., leptin, resistin, adiponectin), and bone also

influence glucose homeostasis.

■ INSULIN BIOSYNTHESIS

Insulin, produced by the beta cells of the pancreatic islets, is initially synthesized as a single-chain 86-amino-acid precursor polypeptide, preproinsulin. Subsequent proteolytic processing removes the

amino-terminal signal peptide, giving rise to proinsulin. Proinsulin is

structurally related to insulin-like growth factors I and II, which bind

weakly to the insulin receptor. Cleavage of an internal 31-residue fragment from proinsulin generates C-peptide with the A (21 amino acids)

and B (30 amino acids) chains of insulin being connected by disulfide

bonds. The mature insulin molecule and C-peptide are stored together

and co-secreted from secretory granules in the beta cells. Because

C-peptide is cleared more slowly than insulin, it is a useful marker of

insulin secretion and allows discrimination of endogenous and exogenous sources of insulin in the evaluation of hypoglycemia (Chaps. 406

and 84). Elevated levels of serum proinsulin have been observed in

both type 1 and 2 DM and are thought to be indicative of beta cell

dysfunction. Pancreatic beta cells co-secrete islet amyloid polypeptide

(IAPP) or amylin, a 37-amino-acid peptide, along with insulin. The

role of IAPP in normal physiology is incompletely defined, but it is the

major component of the amyloid fibrils found in the islets of patients

with type 2 diabetes, and an analogue is sometimes used in treating

type 1 and type 2 DM (Chap. 404).

■ INSULIN SECRETION

Glucose is the key regulator of insulin secretion by the pancreatic beta

cell, although amino acids, ketones, various nutrients, gastrointestinal peptides, and neurotransmitters also influence insulin secretion.

Glucose levels >3.9 mmol/L (70 mg/dL) stimulate insulin synthesis,

primarily by enhancing protein translation and processing. Glucose

stimulation of insulin secretion begins with its transport into the

beta cell by a facilitative glucose transporter (Fig. 403-5). Glucose

phosphorylation by glucokinase is the rate-limiting step that controls

glucose-regulated insulin secretion. Further metabolism of glucose-6-

phosphate via glycolysis generates ATP, which inhibits the activity of

an ATP-sensitive K+ channel. This channel consists of two separate

proteins: one is the binding site for certain oral hypoglycemics (e.g.,

sulfonylureas, meglitinides); the other is an inwardly rectifying K+

channel protein (Kir6.2). Inhibition of this K+ channel induces beta

cell membrane depolarization, which opens voltage-dependent calcium channels (leading to an influx of calcium) and stimulates insulin

secretion. Insulin secretion occurs in two phases, a rapid first-phase

response, and a more prolonged second phase. Impaired first-phase

insulin responses are among the earliest detectable abnormalities

during the progression of both T1DM and T2DM. A number of metabolic pathways internal to the beta cell as well as external cues amplify

glucose-stimulated insulin secretion. Glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic peptide (GIP) are incretin

hormones that bind specific receptors on the beta cell to stimulate

insulin secretion through cyclic AMP production, but they have this

effect only when the blood glucose is above the fasting level. Incretin

hormones also suppress glucagon production and secretion. Incretin

analogues or pharmacologic agents that prolong the activity of endogenous GLP-1 are used to treat type 2 DM. Classically, GLP-1 release was

thought to occur solely from neuroendocrine L-cells of the gastrointestinal tract following food ingestion. However, recent preclinical studies

suggest that intraislet production of GLP-1 from alpha cells may play a

role in the regulation of insulin secretion.

■ INSULIN ACTION

Insulin is secreted into the portal venous system and acts to suppress

endogenous hepatic glucose production and increase hepatic glucose

uptake. A large portion (50%) of secreted insulin is cleared by the liver

in this first pass, yielding a portal to peripheral insulin concentration

gradient of ~2:1, with important implications for the clinical use of

exogenous insulin (Ch. 404). Uncleared insulin enters the systemic circulation where it binds to receptors in peripheral target tissues such as

skeletal muscle and adipose. Insulin binding to its receptor stimulates

Glucose

Insulin

glucagon

Pancreatic islet

Liver

Glucose

production,

storage

Brain

Glucose

utilization

FIGURE 403-4 Regulation of glucose homeostasis. The organs shown contribute

to glucose utilization, production, or storage. See text for a description of the

communications (arrows), which can be neural or humoral. Although not shown,

the GI tract and bone produce factors that influence glucose homeostasis.

+

+

ATP/ADP

Glucose

Glucose

Glucose-6-phosphate

Glucokinase

Pyruvate

Mitochondria

K+ Ca2+

Ca2+

ATP-sensitive

K+ channel

GLUT

Voltage-dependent

Ca2+ channel

Incretins

cAMP

Nucleus

Secretory

granules

Insulin

C peptide

IAPP

Depolarization

Islet

transcription

factors

SUR

Incretin

receptors

FIGURE 403-5 Mechanisms of glucose-stimulated insulin secretion and

abnormalities in diabetes. Glucose and other nutrients regulate insulin secretion

by the pancreatic beta cell. Glucose is transported by a glucose transporter (GLUT1

and/or GLUT2 in humans, GLUT2 in rodents); subsequent glucose metabolism by the

beta cell alters ion channel activity, leading to insulin secretion. The SUR receptor

is the binding site for some drugs that act as insulin secretagogues. Mutations in

the events or proteins underlined are a cause of monogenic forms of diabetes.

ADP, adenosine diphosphate; ATP, adenosine triphosphate; cAMP, cyclic adenosine

monophosphate; IAPP, islet amyloid polypeptide or amylin; SUR, sulfonylurea

receptor.

3099 Diabetes Mellitus: Diagnosis, Classification, and Pathophysiology CHAPTER 403

intrinsic tyrosine kinase activity, leading to receptor autophosphorylation and the recruitment of intracellular signaling molecules, including

the important insulin receptor substrates (IRS). IRS and other adaptor

proteins initiate a complex cascade of phosphorylation and dephosphorylation reactions, resulting in the widespread metabolic and

mitogenic effects of insulin. As an example, activation of the phosphatidylinositol-3′-kinase (PI-3-kinase) pathway stimulates translocation

of a facilitative glucose transporter (e.g., GLUT4) to the cell surface,

an event that is crucial for glucose uptake by skeletal muscle and fat.

Activation of other insulin receptor signaling pathways induces glycogen synthesis, protein synthesis, lipogenesis, and regulation of various

genes in insulin-responsive cells.

PATHOGENESIS

■ TYPE 1 DM

Type 1 DM is the result of interactions of genetic, environmental,

and immunologic factors that ultimately lead to immune-mediated

destruction of the pancreatic beta cells and insulin deficiency. Type 1

DM can develop at any age. Most, but not all, individuals with type 1

DM have evidence of islet-directed autoimmunity, which is detected by

the presence of autoantibodies against beta cell antigens in the blood.

The presence of two or more autoantibodies is now designated as

stage 1 T1DM (Fig. 403-6). The temporal decline of beta cell function

and mass preceding the development of type 1 DM is shown schematically in Fig. 403-6. In susceptible individuals, the autoimmune

process is thought to be triggered by an infectious or environmental

stimulus. In the majority of patients, autoantibodies against beta cell

antigens appear after this triggering event, followed by progressive

loss of insulin secretion. The rate of decline in beta cell function varies

widely among individuals, with some patients progressing rapidly to

clinical diabetes and others evolving to diabetes more slowly and over

a period of several years. Features of diabetes do not become evident

until a threshold loss of insulin secretion and beta cell mass occurs.

Autopsy studies suggest the degree of loss of beta cell mass is variable

at the time of disease presentation. At this point, residual, functional

beta cells exist but are insufficient in number and quality to maintain

glucose tolerance. The events that trigger the transition from glucose

intolerance to frank diabetes are often associated with increased insulin

requirements, as might occur during infections or at puberty. After the

initial clinical presentation of type 1 DM, a “honeymoon” phase may

ensue during which time glycemic control is achieved with modest

doses of insulin or, rarely, insulin is not needed. However, this fleeting

phase of endogenous insulin production from residual beta cells disappears and the individual becomes insulin deficient. Many individuals

with long-standing type 1 DM produce a small amount of insulin (as

reflected by C-peptide production), and autopsy studies show that beta

cells can persist in the pancreas decades after diagnosis.

■ GENETIC CONSIDERATIONS

Susceptibility to type 1 DM involves multiple genes. The concordance of type 1 DM in identical twins ranges from 30–70%, indicating that additional modifying factors are likely involved in

determining whether diabetes develops. The major susceptibility gene

for type 1 DM is located in the HLA region on chromosome 6. Polymorphisms in the HLA complex account for approximately 50% of the

genetic risk of developing type 1 DM. This region contains genes that

encode the class II major histocompatibility complex (MHC) molecules, which present antigen to helper T cells and thus are involved in

initiating the immune response (Chap. 349). The ability of class II

MHC molecules to present antigen is dependent on the amino acid

composition of their antigen-binding sites. Amino acid substitutions

may influence the specificity of the immune response by altering the

binding affinity of different antigens for class II molecules.

Many individuals with type 1 DM have the HLA DR3 and/or DR4

haplotype. Refinements in genotyping of HLA loci have shown that

the haplotypes DQA1*

0301, DQB1*

0302, and DQB1*

0201 are most

strongly associated with type 1 DM. These haplotypes are present in

40% of children with type 1 DM as compared to 2% of the U.S. population without type 1 DM. However, most individuals with predisposing

haplotypes do not develop diabetes.

In addition to MHC class II associations, genome-wide association studies have identified more than 60 additional genetic loci that

contribute susceptibility to type 1 DM (i.e., polymorphisms in the

promoter region of the insulin gene, the CTLA-4 gene, interleukin

2 receptor, and PTPN22, etc.). Combined assessment of HLA and

non-HLA loci using genetic risk scores has been used to improve

prediction of type 1 diabetes risk. Notably, among recent cohorts of

individuals with new-onset type 1 diabetes, there is a decreased representation of the highest-risk HLA alleles and increasing penetrance of

disease in genotypes classically associated with lower risk, suggesting

environmental factors may have an increasing role in disease pathogenesis. Genes that confer protection against the development of the

disease also exist. The haplotype DQA1*0102, DQB1*0602 is extremely

rare in individuals with type 1 DM (<1%) and appears to provide protection from type 1 DM.

Although the risk of developing type 1 DM is increased in relatives

of individuals with the disease, the risk is relatively low: 1–9% if the

parent has type 1 DM and 6–7% in a sibling (depending on which HLA

haplotypes are shared). Hence, the majority of individuals with type 1

DM (>90%) do not have a relative with this disorder.

Pathophysiology Pathologically, the pancreatic islets demonstrate

a modest infiltration of lymphocytes (a process termed insulitis);

however, the frequency of insulitis is heterogeneous both within and

between individuals. Studies of the autoimmune process have identified the following abnormalities in the innate and adaptive arms of

the immune system: (1) islet cell autoantibodies (ICAs); (2) activated

lymphocytes in the islets, and peripancreatic lymph nodes; (3) T lymphocytes that proliferate when stimulated with islet proteins; and (4)

release of cytokines within the insulitis. Islet cell autoantibodies (ICAs)

are a composite of several different antibodies directed at pancreatic

islet molecules such as GAD, insulin, IA-2/ICA-512, and ZnT-8, and

serve as a marker of the autoimmune process of type 1 DM. Testing for

ICAs can be useful in classifying the type of DM as type 1 as they are

Immunologic

trigger

Genetic

predisposition

0

(Birth) Time (years)

Beta cell mass (% of max)

100

50

0

Immunologic abnormalities

Progressive impairment

of insulin release

Stage 3

Overt diabetes

No diabetes

Diabetes

Stage 2

Stage 1

FIGURE 403-6 Temporal model for development of type 1 diabetes. Individuals

with a genetic predisposition are exposed to a trigger that initiates an autoimmune

process, resulting in the development of islet autoantibodies and a gradual decline

in beta cell function and mass. Stage 1 disease is characterized by the development

of two or more islet cell autoantibodies but the maintenance of normoglycemia.

Stage 2 disease is defined by continued autoimmunity and the development

of dysglycemia. Stage 3 is defined by the development of hyperglycemia that

exceeds the diagnostic criteria for the diagnosis of diabetes. The downward slope

of the beta cell function varies among individuals and may not be continuous. A

“honeymoon” phase may be seen in the first 1 or 2 years after the onset of diabetes

and is associated with reduced insulin requirements. (Modified with permission

from ER Kaufman: Medical Management of Type 1 Diabetes, 6th ed. Alexandria, VA:

American Diabetes Association; 2012.)

3100 PART 12 Endocrinology and Metabolism

present in the majority of individuals (>85%) diagnosed with new-onset type 1 DM. ICAs can also identify nondiabetic individuals at risk

for developing type 1 DM, although their use for this purpose has been

restricted mostly to research studies. In children with high genetic risk

followed as part of several birth cohort studies, the presence of two or

more ICAs was associated with a nearly 70% risk of developing type 1

DM after 10 years of follow-up and an 80% risk of developing diabetes

after 15 years of follow-up. These observations led to a revision in the

staging system for type 1 DM (Fig. 403-5), in which the development

of multiple autoantibodies is now defined as the onset of stage 1 type

1 DM. While ICAs can be detected in the serum, and their presence is

an important biomarker of type 1 diabetes risk, the antibodies do not

have a direct role in beta cell death. Beta cell destruction is mediated

by direct CD8+ T cell–mediated cytotoxicity. Beta cells may exacerbate

this process through the development of modified proteins or “neoantigens” and through increased presentation of these antigens on their

cell surface via upregulation of MHC class I molecules. In addition,

beta cells may be damaged by the toxic effects of cytokines (i.e., tumor

necrosis factor α [TNF-α], interferon γ, and interleukin 1 [IL-1]) as

well as reactive oxygen species generated by infiltrating immune cells.

Efforts to suppress the autoimmune process at the time of diagnosis of

diabetes have largely been ineffective or only temporarily effective in

slowing beta cell destruction. Thus, increased emphasis has now been

placed on intervening earlier in the disease course (i.e., during stage

1 and 2 disease; Fig. 403-6). In support of this notion, a single 14-day

course of teplizumab, an Fc receptor-nonbinding anti-CD3 monoclonal antibody, delayed the onset of stage 3 T1D in high-risk individuals

with multiple autoantibodies and dysglycemia (i.e., stage 2 T1D) by a

median of 2.7 years.

Although other islet cell types (alpha cells [glucagon-producing],

delta cells [somatostatin-producing], or PP cells [pancreatic polypeptide-producing]) are functionally and embryologically similar to beta

cells, they are spared from the autoimmune destruction. However,

altered patterns of hormone secretion from these other cell types in

type 1 DM likely contribute to metabolic instability. Alpha cell dysfunction is reflected by fasting and post-prandial hyperglucagonemia

but an impaired glucagon response to hypoglycemia.

Environmental Factors Numerous environmental events have

been proposed to trigger the autoimmune process in genetically

susceptible individuals; however, none has been conclusively linked

to diabetes. Identification of an environmental trigger has been difficult because the event may precede the onset of DM by several years

(Fig. 403-6). Putative environmental triggers include viruses (coxsackie, rubella, enteroviruses most prominently), bovine milk proteins,

nitrosourea compounds, vitamin D deficiency, and environmental toxins. There is increasing interest in the microbiome and type 1 diabetes

(Chap. 471).

■ TYPE 2 DM

Insulin resistance and abnormal insulin secretion are central to the

development of type 2 DM. Although the primary defect is controversial, most studies support the view that insulin resistance precedes an

insulin secretory defect but that diabetes develops only when insulin

secretion becomes inadequate. Type 2 DM likely encompasses a range

of disorders with the common phenotype of hyperglycemia. Historically, our understanding of the pathophysiology and genetics is based

on studies of individuals of European descent. Studies in more diverse

populations have yielded unique insights into pathophysiologic differences among ethnic groups. In general, Latinos have greater insulin

resistance and East Asians and South Asians have more beta cell dysfunction, but both defects are present in both populations. East and

South Asians appear to develop type 2 DM at a younger age and a lower

BMI. In some groups, DM that is ketosis prone (often in obese individuals) or ketosis-resistant (often lean) is sometimes seen. For example,

African Americans can be more prone to nonketotic hyperosmolar

presentation of diabetes exacerbations. In many forms of type 2 DM, the

social determinants of health play a major role in the rates of type 2 DM.

■ GENETIC CONSIDERATIONS

Type 2 DM has a strong genetic component. The concordance of

type 2 DM in identical twins is between 70% and 90%. Individuals

with a parent with type 2 DM have an increased risk of diabetes;

if both parents have type 2 DM, the risk approaches 70%. Insulin resistance, as demonstrated by reduced glucose utilization in skeletal muscle, is present in many nondiabetic, first-degree relatives of individuals

with type 2 DM. The disease is polygenic and multifactorial, because in

addition to genetic susceptibility, environmental factors (such as obesity, poor nutrition, and physical inactivity) modulate the phenotype.

Shared environmental and lifestyle factors also contribute to the high

concordance in families. Further, the in utero environment contributes

to, and either increased or reduced birth weight increases the risk of

type 2 DM in adult life. Children of pregnancies complicated by gestational hyperglycemia also exhibit an increased risk of type 2 DM.

The genes that predispose to type 2 DM are incompletely identified,

but genome-wide association studies have identified a large number of

genes that convey a relatively small risk for type 2 DM (several hundred

genes each with a relative risk of 1.06–1.5). Most prominent is a variant

of the transcription factor 7-like 2 gene that has been associated with

both type 2 DM and IGT in several populations. Genetic polymorphisms associated with type 2 DM have also been found in the genes

encoding the peroxisome proliferator–activated receptor γ, inward rectifying potassium channel, zinc transporter, IRS, and calpain 10. The

mechanisms by which these genetic loci increase the susceptibility to

type 2 DM are not clear, but most are predicted to alter islet function or

development or insulin secretion. Although the genetic susceptibility

to type 2 DM is under active investigation (it is estimated that <10% of

genetic risk is determined by loci identified thus far), it is currently not

possible to use a combination of known genetic loci to reliably predict

type 2 DM.

Pathophysiology Type 2 DM is characterized by impaired insulin

secretion, insulin resistance, excessive hepatic glucose production,

abnormal fat metabolism, and systemic low-grade inflammation.

Obesity, particularly visceral or central (as evidenced by the hipwaist ratio), is very common in type 2 DM (≥80% of patients are

obese). In the early stages of the disorder, glucose tolerance remains

near-normal, despite insulin resistance, because the pancreatic beta

cells compensate by increasing insulin output (Fig. 403-7). A number

Insulin sensitivity

M value (μmol/min per kg)

Insulin secretion

(pmol per min)

1000

500

0

0 50 100

B

C

D

IGT A

NGT

Type 2 DM

FIGURE 403-7 Metabolic changes during the development of type 2 diabetes

mellitus (DM). Insulin secretion and insulin sensitivity are related, and as an

individual becomes more insulin resistant (by moving from point A to point B), insulin

secretion increases. A failure to compensate by increasing the insulin secretion

results initially in impaired glucose tolerance (IGT; point C) and ultimately in type 2

DM (point D). NGT, normal glucose tolerance. (Data from SE Kahn: Clinical review

135: The importance of beta-cell failure in the development and progression of type

2 diabetes. J Clin Endocrinol Metab 86:4047, 2001 and RN Bergman, M Ader: Free

fatty acids and pathogenesis of type 2 diabetes mellitus. Trends Endocrinol Metab

11:351, 2000.)