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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, but most commonly develops before 20 years of age. Most, but not all, individuals with type 1 DM have evidence of islet-directed autoimmunity. However, 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 decline of beta cell function and mass preceding the development of type 1 DM is shown schematically in Fig. 396-6. 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 but may be as high as 70–80%. 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 some individuals with 50 years of type 1 DM have insulin-positive cells in the pancreas at autopsy.
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GENETIC CONSIDERATIONS
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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 (Chap. 343). 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.
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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.
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In addition to MHC class II associations, genome association studies have identified at least 20 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.). 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 those genotypes classically associated with lower risk. 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.
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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 (75%) do not have a first-degree relative with this disorder.
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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 contributes to metabolic instability. Alpha cell dysfunction as reflected by fasting hyperglucagonemia, hyperglucagonemia in the post-prandial state, and an impaired glucagon response to hypoglycemia. Pathologically, the pancreatic islets have 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. Thus, increased emphasis has now been placed on interventions earlier in the disease course (i.e., during Stage 1 and 2 disease; Fig. 396-6).
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Pancreatic islet molecules targeted by the autoimmune process include proinsulin, 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. Stress pathways and processes arising within the beta cell may exacerbate autoimmunity through the development of modified proteins or “neoantigens” that serve as additional immune targets.
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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 and insulin 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. Increasing numbers of autoantibodies are associated with an increased risk of diabetes development. In children with multiple autoantibodies, ~70% developed type 1 DM after 10 years of follow-up, with 80% developing diabetes after 15-year of follow-up. At present, the measurement of ICAs in nondiabetic individuals remains a research tool because no treatments have been demonstrated to prevent the occurrence or progression to type 1 DM.
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Environmental Factors
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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. 396-6). 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. 459).
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Prevention of Type 1 DM
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A number of interventions have prevented diabetes in animal models, but relatively few interventions have been tested in humans in Stages 1 and 2 of type 1 DM. 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. However, this is an area of active clinical investigation with several trials evaluating interventions that target different aspects of the immune response in early stage type 1 DM.
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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. 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 in obese individuals) or ketosis-resistant (often lean) is sometimes seen.
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GENETIC CONSIDERATIONS
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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, poor nutrition, and physical inactivity) 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. 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 (>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. 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.
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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 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. 396-7). 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. Possibly because of inadequate insulin suppression, glucagon is relatively overproduced and secreted, further augmenting hepatic glucose production. 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.
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Metabolic Abnormalities
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ABNORMAL MUSCLE AND FAT METABOLISM
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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 utilization 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.
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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 intermediates 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.
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The obesity accompanying type 2 DM, particularly in a central or visceral location, is thought to be part of the pathogenic process (Chap. 394). 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. 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. The venous drainage of the visceral adipose beds is the portal circulation and this likely contributes to hepatic dysfunction. Free fatty acids also 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.
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IMPAIRED INSULIN SECRETION
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Insulin secretion and sensitivity are interrelated (Fig. 396-7). 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 cell 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.
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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 defects in beta cell function, mass, and potentially cellular identity and differentiation status. Beta cell mass is decreased by ~50% in individuals with long-standing type 2 DM. Islet amyloid polypeptide or amylin, co-secreted by the beta cell, forms amyloid fibrillar deposits 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 also negatively impacts 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, elevated levels of free fatty acids (“lipotoxicity”), and systemic and local elevations in pro-inflammatory cytokines from increased numbers of islet-associated macrophages, may also worsen islet function. Reduced GLP-1 action may contribute to the reduced insulin secretion.
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INCREASED HEPATIC GLUCOSE AND LIPID PRODUCTION
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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 and efficiently cleared by liver leading to increased very-low-density lipoprotein [VLDL]-triglyceride) synthesis in hepatocytes and secretion from liver. 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). If this lipid is retained, steatosis in the liver may lead to nonalcoholic fatty liver disease and abnormal liver function tests.
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Insulin Resistance Syndromes
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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. 401.
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A number of relatively rare forms of severe insulin resistance include features of type 2 DM or IGT (Table 396-1). 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.
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Polycystic ovary syndrome (PCOS) is a common disorder that affects premenopausal women and is characterized by chronic anovulation and hyperandrogenism (Chap. 385). 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.
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Lipodystrophies are group of heterogeneous disorders characterized by selective loss of adipose tissue, leading to severe insulin resistance and hypertriglyceridemia. Lipodystrophies can be inherited or acquired and associated with variable degrees of adipose tissue loss.
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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; the effects of the intervention persisted for at least 15 years. 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 by the Food and Drug Administration 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 suggests 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, and women with a history of GDM). Individuals with IFG, IGT, or an HbA1c of 5.7–6.4% should be monitored annually to determine if diagnostic criteria for diabetes are present.