Chapter 23: Diabetes Mellitus: Diagnosis, Classification, and Pathophysiology

Diabetes mellitus (DM) refers to a group of common metabolic disorders that share the phenotype of hyperglycemia. Several distinct types of DM are caused by a complex interaction of genetics and environmental factors. Depending on the etiology of the DM, factors contributing to hyperglycemia include reduced insulin secretion, decreased glucose utilization, and increased glucose production. The metabolic dysregulation associated with DM causes secondary pathophysiologic changes in multiple organ systems that impose a tremendous burden on the individual with diabetes and on the health care system. In the United States, DM is the leading cause of end-stage renal disease (ESRD), nontraumatic lower extremity amputations, and adult blindness. It also predisposes to cardiovascular diseases. With an increasing incidence worldwide, DM will be likely a leading cause of morbidity and mortality in the future.

DM is classified on the basis of the pathogenic process that leads to hyperglycemia, as opposed to earlier criteria such as age of onset or type of therapy (Fig. 23-1). There are two broad categories of DM, designated type 1 and type 2 (Table 23-1). However, there is increasing recognition of other forms of diabetes in which the pathogenesis is better understood. These other forms of diabetes may share features of type 1 and/or type 2 DM. Both type 1 and type 2 DM are preceded by a phase of abnormal glucose homeostasis as the pathogenic processes progress. Type 1 DM is the result of complete or near-total insulin deficiency. Type 2 DM is a heterogeneous group of disorders characterized by variable degrees of insulin resistance, impaired insulin secretion, and increased glucose production. Distinct genetic and metabolic defects in insulin action and/or secretion give rise to the common phenotype of hyperglycemia in type 2 DM and have important potential therapeutic implications now that pharmacologic agents are available to target specific metabolic derangements. Type 2 DM is preceded by a period of abnormal glucose homeostasis classified as impaired fasting glucose (IFG) or impaired glucose tolerance (IGT).

Two features of the current classification of DM merit emphasis from previous classifications. First, the terms insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) are obsolete. Because many individuals with type 2 DM eventually require insulin treatment for control of glycemia, the use of the term NIDDM generated considerable confusion. A second difference is that age or treatment modality is not a criterion. Although type 1 DM most commonly develops before the age of 30, an autoimmune beta cell destructive process can develop at any age. It is estimated that between 5 and 10% of individuals who develop DM after age 30 years have type 1 DM. Although type 2 DM more typically develops with increasing age, it is now being diagnosed more frequently in children and young adults, particularly in obese adolescents.

OTHER TYPES OF DM

Other etiologies for 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 23-1). 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 can result from pancreatic exocrine disease when the majority of pancreatic islets are destroyed. Cystic fibrosis–related DM is an important consideration in that patient population. Hormones that antagonize insulin action can also lead to DM. Thus, DM 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 islets.

GESTATIONAL DIABETES MELLITUS

Glucose intolerance developing during pregnancy is classified as gestational diabetes mellitus (GDM). Insulin resistance is related to the metabolic changes of late pregnancy, and the increased insulin requirements may lead to IGT or diabetes. GDM occurs in ~7% (range 1–14%) of pregnancies in the United States; most women revert to normal glucose tolerance postpartum but have a substantial risk (35–60%) of developing DM in the next 10–20 years. The International Association of the Diabetes and Pregnancy Study Groups and the American Diabetes Association (ADA) recommend that diabetes diagnosed at the initial prenatal visit should be classified as “overt” diabetes rather than GDM. With the rising rates of obesity, the number of women being diagnosed with GDM or overt diabetes is rising worldwide.

The worldwide prevalence of DM has risen dramatically over the past two decades, from an estimated 30 million cases in 1985 to 382 million in 2013 (Fig. 23-2). Based on current trends, the International Diabetes Federation projects that 592 million individuals will have diabetes by the year 2035 (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 increasing obesity, reduced activity levels as countries become more industrialized, and the aging of the population. In 2013, the prevalence of diabetes in individuals from age 20–79 ranged from 23 to 37% in the 10 countries with the highest prevalence (Tuvalu, Federated States of Micronesia, Marshall Islands, Kiribati, Vanuatu, Cook Islands, Saudi Arabia, Nauru, Kuwait, and Qatar, in descending order of prevalence). The countries with the greatest number of individuals with diabetes in 2013 are China (98.4 million), India (65.1 million), United States (24.4 million), Brazil (11.9 million), and the Russian Federation (10.9 million). Up to 80% of individuals with diabetes live in low-income or medium-income countries. In the most recent estimate for the United States (2012), the Centers for Disease Control and Prevention (CDC) estimated that 9.3% of the population had diabetes (~28% of the individuals with diabetes were undiagnosed; globally, it is estimated that 50% of individuals may be undiagnosed). The CDC estimated that the incidence and prevalence of diabetes doubled from 1990–2008, but appears to have plateaued from 2008–2012. DM increases with age. In 2012, the prevalence of DM in the United Sates was estimated to be 0.2% in individuals age <20 years and 12% in individuals age >20 years. In individuals age >65 years, the prevalence of DM was 26.9%. The prevalence is similar in men and women throughout most age ranges (14% and 11%, respectively, in individuals age >20 years). Worldwide, most individuals with diabetes are between the ages of 40 and 59 years.

There is considerable geographic variation in the incidence of both type 1 and type 2 DM. Scandinavia has the highest incidence of type 1 DM; the lowest incidence is in the Pacific Rim where it is 20- to 30-fold 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 high-risk human leukocyte antigen (HLA) alleles among ethnic groups in different geographic locations. 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; 2010–2012) was 8% in non-Hispanic whites, 9% in Asian Americans, 13% in Hispanics, 13% in non-Hispanic blacks, and 16% 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, and the diabetes phenotype appears to be somewhat different from that in the United States and Europe, 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, but several studies indicate that diabetes is likely underreported as a cause of death. In the United States, diabetes was listed as the seventh leading cause of death in 2010. A recent estimate suggested that diabetes was responsible for almost 5.1 million deaths or 8% of deaths worldwide in 2013. In 2013, it was estimated that $548 billion or 11% of health care expenditures worldwide were spent on individuals with diabetes.

Glucose tolerance is classified into three broad categories: normal glucose homeostasis, DM, or impaired glucose homeostasis. Glucose tolerance can be assessed using the fasting plasma glucose (FPG), the response to oral glucose challenge, or the hemoglobin A_1c (HbA_1c). An FPG <5.6 mmol/L (100 mg/dL), a plasma glucose <140 mg/dL (7.8 mmol/L) following an oral glucose challenge, and an HbA_1c <5.7% are considered to define normal glucose tolerance. The International Expert Committee with members appointed by the ADA, the European Association for the Study of Diabetes, and the International Diabetes Federation have issued diagnostic criteria for DM (Table 23-2) based on the following premises: (1) the FPG, the response to an oral glucose challenge (oral glucose tolerance test [OGTT]), and HbA_1c differ among individuals, and (2) DM is defined as the level of glycemia at which diabetes-specific complications occur rather than on deviations 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. 23-3).

An 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 HbA_1c ≥6.5% warrants the diagnosis of DM (Table 23-2). 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 (Table  23-2).

Abnormal glucose homeostasis (Fig.  23-1) is defined as (1) FPG = 5.6–6.9 mmol/L (100–125 mg/dL), which is defined as impaired fasting glucose (IFG); (2) plasma glucose levels between 7.8 and 11 mmol/L (140 and 199 mg/dL) following an oral glucose challenge, which is termed impaired glucose tolerance (IGT); or (3) HbA_1c of 5.7–6.4%. An HbA_1c of 5.7–6.4%, IFG, and IGT do not identify the same individuals, but 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) for this category. These values for the fasting plasma glucose, the glucose following an oral glucose challenge, and HbA_1c are continuous variables and not discrete categories. The current criteria for the diagnosis of DM emphasize the HbA_1c or 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). OGTT, although still a valid means for diagnosing DM, is not often used in routine clinical care.

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 (Table 23-2). 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 HbA_1c 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, diagnosis of prediabetes should spur efforts for diabetes prevention. The ADA recommends screening all individuals >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 (Table 23-3). In contrast to type 2 DM, a long asymptomatic period of hyperglycemia is rare prior to the diagnosis of type 1 DM. A number of immunologic markers for type 1 DM are becoming available (discussed below), but 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.

OVERALL REGULATION OF GLUCOSE HOMEOSTASIS

Glucose homeostasis reflects a balance between hepatic glucose production and peripheral 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. 23-4). 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 state, low insulin levels increase glucose production by promoting hepatic gluconeogenesis and glycogenolysis and reduce glucose uptake in insulin-sensitive tissues (skeletal muscle and fat), thereby promoting mobilization of stored precursors such as amino acids and free fatty acids (lipolysis). Glucagon, secreted by pancreatic alpha cells when blood glucose or insulin levels are low, stimulates glycogenolysis and gluconeogenesis by the liver and renal medulla (Chap. 26). Postprandially, the glucose load elicits a rise in insulin and fall in glucagon, leading to a reversal of these processes. Insulin, an anabolic hormone, promotes the storage of carbohydrate and fat and protein synthesis. The major portion of postprandial glucose is used by skeletal muscle, an effect of insulin-stimulated glucose uptake. Other tissues, most notably the brain, use glucose in an insulin-independent fashion. Factors secreted by skeletal myocytes (irisin), adipocytes (leptin, resistin, adiponectin, etc.), and bone also influence glucose homeostasis.

INSULIN BIOSYNTHESIS

Insulin is produced in the beta cells of the pancreatic islets. It 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 the C peptide and the A (21 amino acids) and B (30 amino acids) chains of insulin, which are 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. 26 and 28). 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. Human insulin is produced by recombinant DNA technology; structural alterations at one or more amino acid residues modify its physical and pharmacologic characteristics (Chap. 24).

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. 23-5). 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 secretory profiles reveal a pulsatile pattern of hormone release, with small secretory bursts occurring about every 10 min, superimposed upon greater amplitude oscillations of about 80–150 min. Incretins are released from neuroendocrine cells of the gastrointestinal tract following food ingestion and amplify glucose-stimulated insulin secretion and suppress glucagon secretion. Glucagon-like peptide 1 (GLP-1), the most potent incretin, is released from L cells in the small intestine and stimulates insulin secretion only when the blood glucose is above the fasting level. Incretin analogues or pharmacologic agents that prolong the activity of endogenous GLP-1 enhance insulin secretion.

INSULIN ACTION

Once insulin is secreted into the portal venous system, ~50% is removed and degraded by the liver. Unextracted insulin enters the systemic circulation where it binds to receptors in target sites. Insulin binding to its receptor stimulates intrinsic tyrosine kinase activity, leading to receptor autophosphorylation and the recruitment of intracellular signaling molecules, such as 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.

TYPE 1 DM

Type 1 DM is the result of interactions of genetic, environmental, and immunologic factors that ultimately lead to the destruction of the pancreatic beta cells and insulin deficiency. Type 1 DM, which can develop at any age, develops most commonly before 20 years of age. Worldwide, the incidence of type 1 DM is increasing at the rate of 3–4% per year for uncertain reasons. Type 1 DM results from autoimmune beta cell destruction, and most, but not all, individuals have evidence of islet-directed autoimmunity. Some individuals who have the clinical phenotype of type 1 DM lack immunologic markers indicative of an autoimmune process involving the beta cells and the genetic markers of type 1 DM. These individuals are thought to develop insulin deficiency by unknown, nonimmune mechanisms and may be ketosis prone; many are African American or Asian in heritage. The temporal development of type 1 DM is shown schematically as a function of beta cell mass in Fig. 23-6. Individuals with a genetic susceptibility are thought to have normal beta cell mass at birth but begin to lose beta cells secondary to autoimmune destruction that occurs over months to years. This autoimmune process is thought to be triggered by an infectious or environmental stimulus and to be sustained by a beta cell–specific molecule. In the majority of patients, immunologic markers appear after the triggering event but before diabetes becomes clinically overt. Beta cell mass then begins to decrease, and insulin secretion progressively declines, although normal glucose tolerance is maintained. The rate of decline in beta cell mass varies widely among individuals, with some patients progressing rapidly to clinical diabetes and others evolving more slowly. Features of diabetes do not become evident until a majority of beta cells are destroyed (70–80%). At this point, residual functional beta cells exist but are insufficient in number 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 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 some individuals with more than 50 years of type 1 DM have insulin-positive cells in the pancreas at autopsy.

GENETIC CONSIDERATIONS

Susceptibility to type 1 DM involves multiple genes. The concordance of type 1 DM in identical twins ranges between 40 and 60%, 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 40–50% 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. 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.

Most 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 normal U.S. population. However, most individuals with predisposing haplotypes do not develop diabetes.

In addition to MHC class II associations, genome association studies have identified at least 20 different genetic loci that contribute susceptibility to type 1 DM (polymorphisms in the promoter region of the insulin gene, the CTLA-4 gene, interleukin 2 receptor, CTLA4, and PTPN22, etc.). 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 tenfold in relatives of individuals with the disease, the risk is relatively low: 3–4% if the parent has type 1 DM and 5–15% in a sibling (depending on which HLA haplotypes are shared). Hence, most individuals with type 1 DM do not have a first-degree relative with this disorder.

Pathophysiology

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 and express most of the same proteins as beta cells, they are spared from the autoimmune destruction. Pathologically, the pancreatic islets have a modest infiltration of lymphocytes (a process termed insulitis). After beta cells are destroyed, it is thought that the inflammatory process abates and the islets become atrophic. Studies of the autoimmune process in humans and in animal models of type 1 DM (NOD mouse and BB rat) have identified the following abnormalities in the humoral and cellular arms of the immune system: (1) islet cell autoantibodies; (2) activated lymphocytes in the islets, peripancreatic lymph nodes, and systemic circulation; (3) T lymphocytes that proliferate when stimulated with islet proteins; and (4) release of cytokines within the insulitis. Beta cells seem to be particularly susceptible to the toxic effect of some cytokines (tumor necrosis factor α [TNF-α], interferon γ, and interleukin 1 [IL-1]). The precise mechanisms of beta cell death are not known but may involve formation of nitric oxide metabolites, apoptosis, and direct CD8+ T cell cytotoxicity. The islet destruction is mediated by T lymphocytes rather than islet autoantibodies, as these antibodies do not generally react with the cell surface of islet cells and are not capable of transferring DM to animals. 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.

Pancreatic islet molecules targeted by the autoimmune process include insulin, glutamic acid decarboxylase (GAD; the biosynthetic enzyme for the neurotransmitter GABA), ICA-512/IA-2 (homology with tyrosine phosphatases), and a beta cell–specific zinc transporter (ZnT-8). Most of the autoantigens are not beta cell–specific, which raises the question of how the beta cells are selectively destroyed. Current theories favor initiation of an autoimmune process directed at one beta cell molecule, which then spreads to other islet molecules as the immune process destroys beta cells and creates a series of secondary autoantigens. The beta cells of individuals who develop type 1 DM do not differ from beta cells of normal individuals because islets transplanted from a genetically identical twin are destroyed by a recurrence of the autoimmune process of type 1 DM.

Immunologic markers

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. Assays for autoantibodies to GAD-65 are commercially available. Testing for ICAs can be useful in classifying the type of DM as type 1 and in identifying nondiabetic individuals at risk for developing type 1 DM. ICAs are present in the majority of individuals (>85%) diagnosed with new-onset type 1 DM, in a significant minority of individuals with newly diagnosed type 2 DM (5–10%), and occasionally in individuals with GDM (<5%). ICAs are present in 3–4% of first-degree relatives of individuals with type 1 DM. In combination with impaired insulin secretion after IV glucose tolerance testing, they predict a >50% risk of developing type 1 DM within 5 years. At present, the measurement of ICAs in nondiabetic individuals is a research tool because no treatments have been demonstrated to prevent the occurrence or progression to type 1 DM.

Environmental factors

Numerous environmental events have been proposed to trigger the autoimmune process in genetically susceptible individuals; however, none have 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. 23-6). Putative environmental triggers include viruses (coxsackie, rubella, enteroviruses most prominently), bovine milk proteins, and nitrosourea compounds. There is increasing interest in the microbiome and type 1 diabetes.

Prevention of type 1 DM

A number of interventions have prevented diabetes in animal models. None of these interventions have been successful in preventing type 1 DM in humans. For example, the Diabetes Prevention Trial–Type 1 concluded that administering insulin (IV or PO) to individuals at high risk for developing type 1 DM did not prevent type 1 DM. This is an area of active clinical investigation.

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 common phenotype of hyperglycemia. Most of our current understanding (and the discussion below) of the pathophysiology and genetics is based on studies of individuals of European descent. It is becoming increasing apparent that DM in other ethnic groups (Asian, African, and Latin American) has a somewhat different, but yet undefined, pathophysiology. 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 obese) or ketosis-resistant (often lean) is seen.

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 40%. 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, nutrition, and physical activity) modulate the phenotype. The in utero environment also contributes, and either increased or reduced birth weight increases the risk of type 2 DM in adult life. The genes that predispose to type 2 DM are incompletely identified, but recent genome-wide association studies have identified a large number of genes that convey a relatively small risk for type 2 DM (>70 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 type 2 DM in several populations and with IGT in one population at high risk for diabetes. 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 predict type 2 DM.

Pathophysiology

Type 2 DM is characterized by impaired insulin secretion, insulin resistance, excessive hepatic glucose production, and abnormal fat metabolism. Obesity, particularly visceral or central (as evidenced by the hip-waist 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. 23-7). As insulin resistance and compensatory hyperinsulinemia progress, the pancreatic islets in certain individuals are unable to sustain the hyperinsulinemic state. IGT, characterized by elevations in postprandial glucose, then develops. A further decline in insulin secretion and an increase in hepatic glucose production lead to overt diabetes with fasting hyperglycemia. Ultimately, beta cell failure ensues. Although both insulin resistance and impaired insulin secretion contribute to the pathogenesis of type 2 DM, the relative contribution of each varies from individual to individual.

Metabolic Abnormalities

Abnormal muscle and fat metabolism

Insulin resistance, the decreased ability of insulin to act effectively on target tissues (especially muscle, liver, and fat), is a prominent feature of type 2 DM and results from a combination of genetic susceptibility and obesity. Insulin resistance is relative, however, because supranormal levels of circulating insulin will normalize the plasma glucose. Insulin dose-response curves exhibit a rightward shift, indicating reduced sensitivity, and a reduced maximal response, indicating an overall decrease in maximum glucose utilization (30–60% lower than in normal individuals). Insulin resistance impairs glucose utilization by insulin-sensitive tissues and increases hepatic glucose output; both effects contribute to the hyperglycemia. Increased hepatic glucose output predominantly accounts for increased FPG levels, whereas decreased peripheral glucose usage results in postprandial hyperglycemia. In skeletal muscle, there is a greater impairment in nonoxidative glucose usage (glycogen formation) than in oxidative glucose metabolism through glycolysis. Glucose metabolism in insulin-independent tissues is not altered in type 2 DM.

The precise molecular mechanism leading to insulin resistance in type 2 DM has not been elucidated. Insulin receptor levels and tyrosine kinase activity in skeletal muscle are reduced, but these alterations are most likely secondary to hyperinsulinemia and are not a primary defect. Therefore, “postreceptor” defects in insulin-regulated phosphorylation/dephosphorylation appear to play the predominant role in insulin resistance. Abnormalities include the accumulation of lipid within skeletal myocytes, which may impair mitochondrial oxidative phosphorylation and reduce insulin-stimulated mitochondrial ATP production. Impaired fatty acid oxidation and lipid accumulation within skeletal myocytes also may generate reactive oxygen species such as lipid peroxides. Of note, not all insulin signal transduction pathways are resistant to the effects of insulin (e.g., those controlling cell growth and differentiation using the mitogenic-activated protein kinase pathway). Consequently, hyperinsulinemia may increase the insulin action through these pathways, potentially accelerating diabetes-related conditions such as atherosclerosis.

The obesity accompanying type 2 DM, particularly in a central or visceral location, is thought to be part of the pathogenic process (Chap. 20). In addition to these white fat depots, humans now are recognized to have brown fat, which has much greater thermogenic capacity. Efforts are under way to increase the activity or quantity of brown fat (e.g., a myokine, irisin, may convert white to brown fat). The increased adipocyte mass leads to increased levels of circulating free fatty acids and other fat cell products. For example, adipocytes secrete a number of biologic products (nonesterified free fatty acids, retinol-binding protein 4, leptin, TNF-α, resistin, IL-6, and adiponectin). In addition to regulating body weight, appetite, and energy expenditure, adipokines also modulate insulin sensitivity. The increased production of free fatty acids and some adipokines may cause insulin resistance in skeletal muscle and liver. For example, free fatty acids impair glucose utilization in skeletal muscle, promote glucose production by the liver, and impair beta cell function. In contrast, the production by adipocytes of adiponectin, an insulin-sensitizing peptide, is reduced in obesity, and this may contribute to hepatic insulin resistance. Adipocyte products and adipokines also produce an inflammatory state and may explain why markers of inflammation such as IL-6 and C-reactive protein are often elevated in type 2 DM. In addition, inflammatory cells have been found infiltrating adipose tissue. Inhibition of inflammatory signaling pathways such as the nuclear factor-κB (NF-κB) pathway appears to reduce insulin resistance and improve hyperglycemia in animal models and is being tested in humans.

Impaired insulin secretion

Insulin secretion and sensitivity are interrelated (Fig.  23-7). In type 2 DM, insulin secretion initially increases in response to insulin resistance to maintain normal glucose tolerance. Initially, the insulin secretory defect is mild and selectively involves glucose-stimulated insulin secretion, including a greatly reduced first secretory phase. The response to other nonglucose secretagogues, such as arginine, is preserved, but overall beta function is reduced by as much as 50% at the onset of type 2 DM. Abnormalities in proinsulin processing are reflected by increased secretion of proinsulin in type 2 DM. Eventually, the insulin secretory defect is progressive.

The reason(s) for the decline in insulin secretory capacity in type 2 DM is unclear. The assumption is that a second genetic defect—superimposed upon insulin resistance—leads to beta cell failure. Beta cell mass is decreased by approximately 50% in individuals with long-standing type 2 DM. Islet amyloid polypeptide or amylin, co-secreted by the beta cell, forms the amyloid fibrillar deposit found in the islets of individuals with long-standing type 2 DM. Whether such islet amyloid deposits are a primary or secondary event is not known. The metabolic environment of diabetes may also negatively impact islet function. For example, chronic hyperglycemia paradoxically impairs islet function (“glucose toxicity”) and leads to a worsening of hyperglycemia. Improvement in glycemic control is often associated with improved islet function. In addition, elevation of free fatty acid levels (“lipotoxicity”) and dietary fat may also worsen islet function. Reduced GLP-1 action may contribute to the reduced insulin secretion.

Increased hepatic glucose and lipid production

In type 2 DM, insulin resistance in the liver reflects the failure of hyperinsulinemia to suppress gluconeogenesis, which results in fasting hyperglycemia and decreased glycogen storage by the liver in the postprandial state. Increased hepatic glucose production occurs early in the course of diabetes, although likely after the onset of insulin secretory abnormalities and insulin resistance in skeletal muscle. As a result of insulin resistance in adipose tissue, lipolysis and free fatty acid flux from adipocytes are increased, leading to increased lipid (very-low-density lipoprotein [VLDL] and triglyceride) synthesis in hepatocytes. This lipid storage or steatosis in the liver may lead to nonalcoholic fatty liver disease and abnormal liver function tests. This is also responsible for the dyslipidemia found in type 2 DM (elevated triglycerides, reduced high-density lipoprotein [HDL], and increased small dense low-density lipoprotein [LDL] particles).

Insulin resistance syndromes

The insulin resistance condition comprises a spectrum of disorders, with hyperglycemia representing one of the most readily diagnosed features. The metabolic syndrome, the insulin resistance syndrome, and syndrome X are terms used to describe a constellation of metabolic derangements that includes insulin resistance, hypertension, dyslipidemia (decreased HDL and elevated triglycerides), central or visceral obesity, type 2 DM or IGT/IFG, and accelerated cardiovascular disease. This syndrome is discussed in Chap. 22.

A number of relatively rare forms of severe insulin resistance include features of type 2 DM or IGT (Table 23-1). Mutations in the insulin receptor that interfere with binding or signal transduction are a rare cause of insulin resistance. Acanthosis nigricans and signs of hyperandrogenism (hirsutism, acne, and oligomenorrhea in women) are also common physical features. Two distinct syndromes of severe insulin resistance have been described in adults: (1) type A, which affects young women and is characterized by severe hyperinsulinemia, obesity, and features of hyperandrogenism; and (2) type B, which affects middle-aged women and is characterized by severe hyperinsulinemia, features of hyperandrogenism, and autoimmune disorders. Individuals with the type A insulin resistance syndrome have an undefined defect in the insulin-signaling pathway; individuals with the type B insulin resistance syndrome have autoantibodies directed at the insulin receptor. These receptor autoantibodies may block insulin binding or may stimulate the insulin receptor, leading to intermittent hypoglycemia.

Polycystic ovary syndrome (PCOS) is a common disorder that affects premenopausal women and is characterized by chronic anovulation and hyperandrogenism (Chap. 13). Insulin resistance is seen in a significant subset of women with PCOS, and the disorder substantially increases the risk for type 2 DM, independent of the effects of obesity.

Prevention

Type 2 DM is preceded by a period of IGT or IFG, and a number of lifestyle modifications and pharmacologic agents prevent or delay the onset of DM. Individuals with prediabetes or increased risk of diabetes should be referred to a structured program to reduce body weight and increase physical activity as well as being screened for cardiovascular disease. The Diabetes Prevention Program (DPP) demonstrated that intensive changes in lifestyle (diet and exercise for 30 min/d five times/week) in individuals with IGT prevented or delayed the development of type 2 DM by 58% compared to placebo. This effect was seen in individuals regardless of age, sex, or ethnic group. In the same study, metformin prevented or delayed diabetes by 31% compared to placebo. The lifestyle intervention group lost 5–7% of their body weight during the 3 years of the study. Studies in Finnish and Chinese populations noted similar efficacy of diet and exercise in preventing or delaying type 2 DM. A number of agents, including α-glucosidase inhibitors, metformin, thiazolidinediones, GLP-1 receptor pathway modifiers, and orlistat, prevent or delay type 2 DM but are not approved for this purpose. Individuals with a strong family history of type 2 DM and individuals with IFG or IGT should be strongly encouraged to maintain a normal BMI and engage in regular physical activity. Pharmacologic therapy for individuals with prediabetes is currently controversial because its cost-effectiveness and safety profile are not known. The ADA has suggested that metformin be considered in individuals with both IFG and IGT who are at very high risk for progression to diabetes (age <60 years, BMI ≥35 kg/m², family history of diabetes in first-degree relative, and women with a history of GDM). Individuals with IFG, IGT, or an HbA_1c of 5.7–6.4% should be monitored annually to determine if diagnostic criteria for diabetes are present.

Several monogenic forms of DM have been identified. More than 10 different variants of MODY, caused by mutations in genes encoding islet-enriched transcription factors or glucokinase (Fig. 23-5; Table 23-1), are transmitted as autosomal dominant disorders. MODY 1, MODY 3, and MODY 5 are caused by mutations in hepatocyte nuclear transcription factor (HNF) 4α, HNF-1α, and HNF-1β, respectively. As their names imply, these transcription factors are expressed in the liver but also in other tissues, including the pancreatic islets and kidney. These factors most likely affect islet development or the expression of genes important in glucose-stimulated insulin secretion or the maintenance of beta cell mass. For example, individuals with an HNF-1α mutation (MODY 3) have a progressive decline in glycemic control but may respond to sulfonylureas. In fact, some of these patients were initially thought to have type 1 DM but were later shown to respond to a sulfonylurea, and insulin was discontinued. Individuals with a HNF-1β mutation have progressive impairment of insulin secretion and hepatic insulin resistance, and require insulin treatment (minimal response to sulfonylureas). These individuals often have other abnormalities such as renal cysts, mild pancreatic exocrine insufficiency, and abnormal liver function tests. Individuals with MODY 2, the result of mutations in the glucokinase gene, have mild-to-moderate, stable hyperglycemia that does not respond to oral hypoglycemic agents. Glucokinase catalyzes the formation of glucose-6-phosphate from glucose, a reaction that is important for glucose sensing by the beta cells (Fig. 23-5) and for glucose utilization by the liver. As a result of glucokinase mutations, higher glucose levels are required to elicit insulin secretory responses, thus altering the set point for insulin secretion. Studies of populations with type 2 DM suggest that mutations in MODY-associated genes are an uncommon (<5%) cause of type 2 DM. Mutations in mitochondrial DNA are associated with diabetes and deafness.

Transient or permanent neonatal diabetes (onset <12 months of age) occurs. Permanent neonatal diabetes may be caused by several genetic mutations, usually requires treatment with insulin, and phenotypically is similar to type 1 DM. Mutations in the ATP-sensitive potassium channel subunits (Kir6.2 and ABCC8) and the insulin gene (interfere with proinsulin folding and processing) (Fig.  23-5) are the major causes of permanent neonatal diabetes. Although these activating mutations in the ATP-sensitive potassium channel subunits impair glucose-stimulated insulin secretion, these individuals may respond to sulfonylureas and can be treated with these agents. These mutations are often associated with a spectrum of neurologic dysfunction. MODY 4 is a rare variant caused by mutations in the insulin promoter factor (IPF) 1, a transcription factor that regulates pancreatic development and insulin gene transcription. Homozygous inactivating mutations cause pancreatic agenesis, whereas heterozygous mutations may result in DM. Mutations in the transcription factor of GATA6 are the most common cause of pancreatic agenesis. Homozygous glucokinase mutations cause a severe form of neonatal diabetes.

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