Harrison's Principle of Internal Medicine 17 Ed. 2008
INTRODUCTION
Diabetes mellitus (DM) refers to a group of common metabolic disorders that share the phenotype of hyperglycemia. Several distinct types of DM exist and 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
CLASSIFICATION
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. 1). The two broad categories of DM are designated type 1 and type 2 (Table 1). Both types of diabetes are preceded by a phase of abnormal glucose homeostasis as the pathogenic processes progresses. Type 1 diabetes 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).
Figure 1. Spectrum of glucose homeostasis and diabetes mellitus (DM). The spectrum from normal glucose tolerance to diabetes in type 1 DM, type 2 DM, other specific types of diabetes, and gestational DM is shown from left to right. In most types of DM, the individual traverses from normal glucose tolerance to impaired glucose tolerance to overt diabetes. Arrows indicate that changes in glucose tolerance may be bi-directional 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 even normal glucose tolerance after delivery. The fasting plasma glucose (FPG) and 2-h plasma glucose (PG), after a glucose challenge for the different categories of glucose tolerance, are shown at the lower part of the figure. These values do not apply to the diagnosis of gestational DM. Some types of DM may or may not require insulin for survival, hence the dotted line. (Conventional units are used in the figure.) (Adapted from the American Diabetes Association, 2007.)
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| Note: MODY, maturity onset of diabetes of the young. Source: Adapted from American Diabetes Association, 2007. |
Two features of the current classification of DM diverge from previous classifications. First, the terms insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM) are obsolete. Since 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 is not a criterion in the classification system. 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 have type 1 DM. Likewise, type 2 DM more typically develops with increasing age but 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 1). Maturity onset diabetes of the young (MODY) is a subtype of DM characterized by autosomal dominant inheritance, early onset of hyperglycemia (usually <25>
DM can result from pancreatic exocrine disease when the majority of pancreatic islets are destroyed. 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
Gestational Diabetes Mellitus (GDM)
Glucose intolerance may develop during pregnancy. Insulin resistance is related to the metabolic changes of late pregnancy, and the increased insulin requirements may lead to IGT. GDM occurs in ~4% of pregnancies in the
EPIDEMIOLOGY
The worldwide prevalence of DM has risen dramatically over the past two decades, from an estimated 30 million cases in 1985 to 177 million in 2000. Based on current trends, >360 million individuals will have diabetes by the year 2030 (Fig. 2). 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 because of increasing obesity and reduced activity levels as countries become more industrialized. This is true in most countries, and 6 of the top 10 countries with the highest rates are in
Figure 2. Worldwide prevalence of diabetes mellitus. The prevalence of diabetes in 2000 and the projected prevalence in 2030 are shown by geographical region. (Used with permission from Diabetes Action Now: An Initiative of the World Health Organization and the International Diabetes Federation, 2004, as adapted from S Wild et al: Diabetes Care 27:1047, 2004.)
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 (e.g., in Finland, the incidence is 35/100,000 per year). The Pacific Rim has a much lower rate (in
Diabetes is a major cause of mortality, but several studies indicate that diabetes is likely underreported as a cause of death. In the
DIAGNOSIS
The National Diabetes Data Group and World Health Organization have issued diagnostic criteria for DM (Table 2) based on the following premises: (1) the spectrum of fasting plasma glucose (FPG) and the response to an oral glucose load (OGTT—oral glucose tolerance test) varies among normal 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 a FPG > 6.4 mmol/L (116 mg/dL) (Fig. 3).
Figure 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 glycated hemoglobin (A1C). Note that the incidence of retinopathy greatly increases at a fasting plasma glucose >116 mg/dL, or a 2-h plasma glucose of 185 mg/dL, or a A1C >6.0%. (Blood glucose values are shown in mg/dL; to convert to mmol/L, divide value by 18.) (Copyright 2002, American Diabetes Association. From Diabetes Care 25(Suppl 1): S5–S20, 2002.)
Glucose tolerance is classified into three categories based on the FPG (Fig. 1): (1) FPG < fpg =" 5.6–6.9"> >7.0 mmol/L (126 mg/dL) warrants the diagnosis of DM. Based on the OGTT, IGT is defined as plasma glucose levels between 7.8 and 11.1 mmol/L (140 and 199 mg/dL) and diabetes is defined as a glucose > 11.1 mmol/L (200 mg/dL) 2 h after a 75-g oral glucose load (Table 2). Some individuals have both IFG and IGT. Individuals with IFG and/or IGT, recently designated pre-diabetes by the American Diabetes Association (ADA), are at substantial risk for developing type 2 DM (25–40% risk over the next 5 years) and have an increased risk of cardiovascular disease.
The current criteria for the diagnosis of DM emphasize that the FPG is the most reliable and convenient test for identifying DM in asymptomatic individuals. A random plasma glucose concentration >11.1 mmol/L (200 mg/dL) accompanied by classic symptoms of DM (polyuria, polydipsia, weight loss) is sufficient for the diagnosis of DM (Table 2). Oral glucose tolerance testing, although still a valid means for diagnosing DM, is not recommended as part of routine care.
Some investigators have advocated the hemoglobin A1C (A1C) as a diagnostic test for DM. Though there is a strong correlation between elevations in the plasma glucose and the A1C (discussed below), the relationship between the FPG and the A1C in individuals with normal glucose tolerance or mild glucose intolerance is less clear, and thus the use of the A1C is not currently recommended to diagnose diabetes.
The diagnosis of DM has profound implications for an individual from both a medical and financial standpoint. Thus, these diagnostic criteria must be satisfied before assigning the diagnosis of DM. 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 2). The revised criteria also allow for the diagnosis of DM to be withdrawn in situations where the FPG reverts to normal.
Screening
Widespread use of the FPG 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) as many as 50% of individuals with type 2 DM have one or more diabetes-specific complications at the time of their diagnosis, and (4) treatment of type 2 DM may favorably alter the natural history of DM. The ADA recommends screening all individuals >45 years every 3 years and screening individuals at an earlier age if they are overweight [body mass index (BMI) > 25 km/m2] and have one additional risk factor for diabetes (Table 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 is discouraged pending the identification of clinically beneficial interventions for individuals at high risk for developing type 1 DM.
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| Note: BMI, body mass index; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; GDM, gestational diabetes mellitus; HDL, high-density lipoprotein. Source: Adapted from American Diabetes Association, 2007. |
PATOGENESIS
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 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. These individuals are thought to develop insulin deficiency by unknown, nonimmune mechanisms and are 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. 3. Individuals with a genetic susceptibility 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, immunologic markers appear after the triggering event but before diabetes becomes clinically overt. Beta cell mass then begins to decline, and insulin secretion becomes progressively impaired, 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 (~80%). At this point, residual functional beta cells still 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 as the autoimmune process destroys the remaining beta cells, and the individual becomes completely insulin deficient.
Figure 4. Temporal model for development of type 1 diabetes. Individuals with a genetic predisposition are exposed to an immunologic trigger that initiates an autoimmune process, resulting in a gradual decline in beta cell mass. The downward slope of the beta cell mass varies among individuals and may not be continuous. This progressive impairment in insulin release results in diabetes when ~80% of the beta cell mass is destroyed. 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. [Adapted from Medical Management of Type 1 Diabetes, 3d ed, JS Skyler (ed). American Diabetes Association,
Genetic Considerations
Susceptibility to type 1 DM involves multiple genes. The concordance of type 1 DM in identical twins ranges between 30 and 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 40–50% of the genetic risk of developing type 1 DM. This region contains genes that encode the class II MHC molecules, which present antigen to helper T cells and thus are involved in initiating the immune response (Chap. 309). 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
In addition to MHC class II associations, at least 10 different genetic loci contribute susceptibility to type 1 DM (loci recently identified include polymorphisms in the promoter region of the insulin gene, the CTLA-4 gene, interleukin-2 receptor, IFIH1, and PTPN22). 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%)>
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 diabetes 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 inexplicably spared from the autoimmune process. Pathologically, the pancreatic islets are infiltrated with lymphocytes (in a process termed insulitis). After all beta cells are destroyed, the inflammatory process abates, the islets become atrophic, and most immunologic markers disappear. 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. Suppression of the autoimmune process (cyclosporine, T lymphocyte antibodies) at the time of diagnosis of diabetes slows the decline in beta cell destruction, but the safety of such interventions is unknown.
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 phogrin (insulin secretory granule protein). With the exception of insulin, none of the autoantigens are 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, since 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, and IA-2/ICA-512 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 (>75%) 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%).>50% risk of developing type 1 DM within 5 years. Without this impairment in insulin secretion, the presence of ICAs predicts a 5-year risk of <25%.>
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. 3). Putative environmental triggers include viruses (coxsackie and rubella most prominently), bovine milk proteins, and nitrosourea compounds.
A number of interventions have successfully delayed or prevented diabetes in animal models. Some interventions have targeted the immune system directly (immunosuppression, selective T cell subset deletion, induction of immunologic tolerance to islet proteins), whereas others have prevented islet cell death by blocking cytotoxic cytokines or increasing islet resistance to the destructive process. Though results in animal models are promising, these interventions have not been successful in preventing type 1 DM in humans. The Diabetes Prevention Trial—type 1 concluded that administering insulin (IV or
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 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 since in addition to genetic susceptibility, environmental factors (such as obesity, nutrition, and physical activity) modulate the phenotype. The genes that predispose to type 2 DM are incompletely identified, but recent genome-wide association studies have identified several genes that convey a relatively small risk for type 2 DM (relative risk of 1.1-1.5). Most prominent is a variant of the transcription factor 7-like 2 gene that has been associated with type 2 diabetes in several populations and with impaired glucose tolerance in one population at high risk for diabetes. Genetic polymorphisms associated with type 2 diabetes have also been found in the genes encoding the peroxisome proliferators-activated receptor-γ, inward rectifying potassium channel expressed in beta cells, zinc transporter expressed in beta cells, IRS, and calpain 10. The mechanisms by which these genetic alterations increase the susceptibility to type 2 diabetes are not clear, but several are predicted to alter insulin secretion. Investigation using genome-wide scanning for polymorphisms associated with type 2 DM is ongoing.
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. 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. 4). 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 may ensue.
Figure 5. 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). (Adapted from SE Kahn: J Clin Endocrinol Metab 86:4047, 2001; RN Bergman, M Ader: Trends Endocrinol Metab 11:351, 2000.)
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, since supernormal 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 may play the predominant role in insulin resistance (Fig. 2-insulin biosynthesis). For example, a PI-3-kinase signaling defect may reduce translocation of GLUT4 to the plasma membrane. Other 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 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. The increased adipocyte mass leads to increased levels of circulating free fatty acids and other fat cell products (Chap. 74). For example, adipocytes secrete a number of biologic products (nonesterified free fatty acids, retinol-binding protein 4, leptin, TNF-α, resistin, 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. Inhibition of inflammatory signaling pathways such as the nuclear factor κB (NFκB) pathway appears to reduce insulin resistance and improve hyperglycemia in animal models.
Impaired Insulin Secretion
Insulin secretion and sensitivity are interrelated (Fig. 4). 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. The response to other nonglucose secretagogues, such as arginine, is preserved. Eventually, the insulin secretory defect progresses to a state of grossly inadequate insulin secretion.
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. Islet amyloid polypeptide or amylin is cosecreted by the beta cell and 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. Beta cell mass is decreased in individuals with long-standing type 2 diabetes.
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, though likely after the onset of insulin secretory abnormalities and insulin resistance in skeletal muscle. As a result of insulin resistance in adipose tissue and obesity, free fatty acid (FFA) flux from adipocytes is 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 (Chap. 303) 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, or syndrome X are terms used to describe a constellation of metabolic derangements that includes insulin resistance, hypertension, dyslipidemia (low HDL and elevated triglycerides), central or visceral obesity, type 2 diabetes or IGT/IFG, and accelerated cardiovascular disease. This syndrome is discussed in Chap. 236.
A number of relatively rare forms of severe insulin resistance include features of type 2 DM or IGT (Table 1). 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. 341). 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, and a number of lifestyle modifications and pharmacologic agents prevent or delay the onset of DM. The Diabetes Prevention Program (DPP) demonstrated that intensive changes in lifestyle (diet and exercise for 30 min/day 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; acarbose, metformin, thiazolidinediones, and orlistat prevent or delay type 2 DM but are not approved for this purpose. When administered to nondiabetic individuals for other reasons (cardiac, cholesterol lowering, etc.), pravastatin reduced the number of new cases of diabetes. 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. A recent ADA Consensus panel concluded that metformin, but not other medications, could be considered in individuals with both IFG and IGT who are at very high risk for progression to diabetes (age <>35 kg/m2, family history of diabetes in first-degree relative, elevated triglycerides, reduced HDL, hypertension, or A1C > 6.0%).