448 Insulin Resistance and Secretion in Type 2 Diabetes Mayo Clin Proc, April 2003, Vol 78 Table 1. Factors Regulating Glucose Homeostasis Insulin-ind

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1 Mayo Clin Proc, April 2003, Vol 78 Insulin Resistance and Secretion in Type 2 Diabetes 447 Review Contributions of Insulin-Resistance and Insulin-Secretory Defects to the Pathogenesis of Type 2 Diabetes Mellitus JOHN E. GERICH, MD Controlled clinical trials have shown that optimal glycemic control can prevent the microvascular complications of type 2 diabetes mellitus; considerable epidemiological data suggest that this may also be true for macrovascular complications. However, this is frequently not achieved. Consequently, research efforts have been undertaken to better understand the pathophysiology of this disorder. It is now well recognized that 2 factors are involved: impaired β-cell function and insulin resistance. Prospective studies of high-risk populations have shown insulin-resistance and/ or insulin-secretory defects before the onset of impaired glucose tolerance. Thus, there has been a long-standing debate whether an alteration in insulin sensitivity or in insulin secretion is the primary genetic factor. Most of the available evidence favors the view that type 2 diabetes is a heterogeneous disorder in which the major genetic factor is impaired β-cell function and insulin resistance is the major acquired factor. Superimposition of insulin resistance on a β cell that cannot appropriately compensate leads to deterioration in glucose tolerance. Therefore, clinicians managing type 2 diabetes must reduce insulin resistance and augment and/or replace β-cell function. Mayo Clin Proc. 2003;78: DCCT = Diabetes Control and Complications Trial; FFA = free fatty acid; UKPDS = United Kingdom Prospective Diabetes Study An estimated 16 million individuals in the United States are thought to have diabetes, a number that is expected to double by Type 2 diabetes mellitus (previously called non insulin-dependent diabetes mellitus or adult-onset diabetes) accounts for about 85% to 90% of cases of diabetes and is a major health problem of increasing magnitude as the US population ages and becomes more obese. 2,3 Worldwide, the incidence of type 2 diabetes also is increasing among children, representing a growing pediatric epidemic. 4 The macrovascular and microvascular complications of type 2 diabetes cause pronounced morbidity and mortality (blindness, kidney failure, amputation, and death due to cardiovascular disease) and account for a substantial portion of the economic burden imposed by the disorder. The Diabetes Control and Complications Trial (DCCT), published in 1993, showed that the use of intensive insulin therapy for type 1 diabetes prevents the onset and slows the progression of retinopathy, nephropathy, and neuropathy. 5 The United Kingdom Prospective Diabetes Study (UKPDS), another landmark study in the field of diabetes, was initiated in 1977 to assess the benefits of aggressive glycemic control specifically in patients with type 2 diabe- From the Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY. Individual reprints of this article are not available. Address correspondence to John E. Gerich, MD, Department of Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Box MED/CRC, Rochester, NY tes. 6,7 During a 10-year period, intensive treatment with sulfonylureas, metformin, and insulin alone or in combination produced an 11% difference in median hemoglobin A 1c levels between intensively and conventionally treated groups (7.0% vs 7.9%). This modest difference was associated with a significant 25% 10-year risk reduction in microvascular disease and a 16% 10-year risk reduction in nonfatal-fatal myocardial infarction. 8 Every percentage point decrease in hemoglobin A 1c (eg, from 9% to 8%) reduced the risk of microvascular complications and diabetes-related deaths by 37% and 21%, respectively. 8 For editorial comment, see page 411. On the basis of the results of the DCCT and UKPDS, the American Diabetes Association recommends that hemoglobin A 1c levels be maintained below 7.0%. 2 The American Association of Clinical Endocrinology recommends a target lower than 6.5%. 9 Current management of type 2 diabetes usually does not achieve this goal. 10 Therefore, efforts are under way to delineate the pathophysiologic and molecular events underlying type 2 diabetes to develop more effective treatment strategies. One outcome of these ongoing research efforts is the recognition that regulating plasma glucose levels depends on a carefully orchestrated interaction between insulindependent and insulin-independent mechanisms (Table 1). Glucose itself can alter its own metabolism; thus, increases in plasma glucose levels decrease gluconeogenesis, promote glucose uptake, and reduce lipolysis even in the ab- Mayo Clin Proc. 2003;78: Mayo Foundation for Medical Education and Research

2 448 Insulin Resistance and Secretion in Type 2 Diabetes Mayo Clin Proc, April 2003, Vol 78 Table 1. Factors Regulating Glucose Homeostasis Insulin-independent mechanisms Glucose uptake and utilization by insulin-insensitive tissues (eg, brain) Glucose autoregulation Increase glucose uptake Inhibit lipolysis Suppress glucose production Insulin-mediated mechanisms Glucose uptake in skeletal muscle Glucose release and storage in liver Inhibit gluconeogenesis Inhibit glycogenolysis Glucose uptake and inhibition of lipolysis in adipocytes Other factors that affect glucose regulation either through insulin-dependent or insulin-independent mechanisms Glucagon Cortisol Epinephrine Growth hormone Free fatty acids Leptin Tumor necrosis factor α Resistin Adiponectin Table 2. ATP III Criteria for Identifying the Metabolic Syndrome* Risk factor Abdominal obesity (waist circumference) Men Women Plasma triglycerides Plasma high-density lipoprotein cholesterol Men Women Blood pressure Fasting plasma glucose Defining level >40 in >35 in 150 mg/dl <40 mg/dl <50 mg/dl 130/ 85 mm Hg 110 mg/dl *ATP III = Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 41 Persons with 3 of the 5 risk factors are considered to have the metabolic syndrome. sence of a concomitant increase in plasma insulin levels. 11 Insulin-insensitive tissues such as the brain contribute substantially to glucose disposal, especially in the fasting state. 12,13 Insulin-dependent regulation of glucose homeostasis is subject to tight feedback control because β-cell insulin secretion is regulated by changes in plasma glucose concentrations and by the insulin sensitivity of target tissues. 14,15 Other hormones and substrates in addition to insulin, including glucagon, catecholamines, cortisol, and free fatty acids (FFAs), participate in the regulation of glucose metabolism either by altering the insulin signal transduction or by directly affecting metabolic pathways. 16,17 Insulin resistance, a decrease in the response of target tissues to insulin, has been associated with type 2 diabetes since the 1930s. At that time, Himsworth and Kerr characterized obese patients with type 2 diabetes as insulin insensitive on the basis of their plasma glucose responses to exogenous insulin compared with those of lean, nondiabetic individuals. 18 Furthermore, it has been established since 1960 that fasting plasma insulin levels are often elevated in obese insulin-insensitive patients with type 2 diabetes in contrast to the low insulin levels associated with type 1 diabetes. 18 These elevated insulin levels are inappropriately low for the plasma glucose levels, indicating the presence also of impaired β-cell function. 19 Subsequent studies confirmed the presence of a variety of insulin-secretory defects not only in patients with type 2 diabetes but also in glucose-tolerant individuals at high risk for developing the disease due to family history or ethnicity. 21,25,26-34 The discovery that obesity causes insulin resistance and the fact that more than 80% of patients with type 2 diabetes are obese provided support for the theory that obesity is the major cause of insulin resistance in type 2 diabetes. 11,15,21,35 Thus, it is now well established that both β-cell dysfunction and insulin resistance play critical roles in the etiology of type 2 diabetes. TYPE 2 DIABETES MELLITUS AS AN INSULIN-RESISTANT CONDITION Insulin resistance is associated with a cluster of metabolic abnormalities known collectively as the insulin resistance syndrome, the metabolic syndrome, or syndrome X Recently, the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) published criteria to identify the syndrome according to the following major components: abdominal obesity, hypertension, dyslipidemia, and abnormal glucose tolerance (Table 2). 41 Approximately 47 million Americans are estimated to have some combination of the factors that comprise the insulin resistance syndrome. 42 This syndrome has also been linked to a markedly increased risk for cardiovascular disease Insulin resistance impedes glucose disposal and disrupts lipid metabolism in insulin-sensitive tissues, particularly muscle, the liver, and adipose tissue. 12,18,35,43,44 In muscle, the condition manifests as inefficient glucose transport with subsequent impaired uptake, oxidation, and storage (as glycogen). 12,18,35,44 In the liver, insulin resistance reduces postprandial glucose storage and the suppression of glycogenolysis and gluconeogenesis in the fasting and postprandial states. 35,43 The ability of insulin to inhibit lipolysis in adipose tissue is also impaired. 12,43,44 Insulin Resistance in Patients With Type 2 Diabetes Mellitus and High-Risk Populations Insulin resistance is a common condition. Data from the Insulin Resistance Atherosclerosis Study indicate that

3 Mayo Clin Proc, April 2003, Vol 78 Insulin Resistance and Secretion in Type 2 Diabetes 449 Table 3. Selected Studies of Insulin Resistance in High-Risk Populations Reference Population Glycemic status Key findings Lillioja et al, Pima Indians Nondiabetic Prospective study showed insulin resistance was a strong predictor of type 2 diabetes Martin et al, Children of parents who both Normal glucose Obese subjects who developed type 2 diabetes had decreased have type 2 diabetes tolerance insulin sensitivity >10 y before symptoms; cumulative incidence of type 2 diabetes in obese subjects = 76% Gulli et al, Offspring of Mexican American Normal glucose At-risk obese subjects showed hyperinsulinemia in fasting state and parents who both have type 2 tolerance during oral glucose tolerance test, decreased glucose disposal, and diabetes decreased insulin-mediated suppression of oxidation Warram et al, Children of parents who both Normal glucose At-risk obese subjects had decreased glucose removal rate and have type 2 diabetes tolerance hyperinsulinemia >1 decade before type 2 diabetes; insulin resistance predicted diabetes more than 90% of obese Caucasians, African Americans, and Hispanic Americans with type 2 diabetes could be classified as insulin insensitive. 45 Studies in populations at high risk for developing diabetes (eg, obese American Indians) have shown that insulin resistance is detectable in the earliest stages of deterioration of glucose tolerance and in obese glucose-tolerant individuals at high risk for developing diabetes later in life (Table 3) The Pima Indians of Arizona, who are obese and have a disproportionately high incidence of type 2 diabetes, have served as subjects in several studies of insulin resistance and insulin secretion during the prediabetic phase. 46,50 A prospective study that followed up 200 obese Pima Indians for a mean of 5.3 years found that insulin resistance was a strong predictor of type 2 diabetes. 46 Evidence of insulin resistance in conjunction with hyperinsulinemia also has been identified more than a decade before the onset of diabetes in the obese offspring of individuals with type 2 diabetes Insulin resistance in this setting, as in the Pima Indian population, 46 significantly increased the risk of developing diabetes. 47,49 In a study of 155 individuals whose parents both had type 2 diabetes, the 25-year incidence of type 2 diabetes was 76% among obese individuals with insulin resistance. 47 Although these studies show the importance of insulin resistance as a risk factor for developing type 2 diabetes, they have been criticized for not properly assessing β-cell function and for not distinguishing between obesity and genetics as a cause of the insulin resistance. 51,52 Genetic and Environmental Mechanisms of Insulin Resistance Genetic Influences. The studies of high-risk populations imply that insulin resistance, like type 2 diabetes itself, has a genetic component and that heritable differences in insulin sensitivity may be one element of a susceptibility genotype predisposing members of high-risk populations to type 2 diabetes. 53,54 Additional evidence of genetic effects is derived from twin studies that provide estimates ranging from 47% to 66% for the heritability of insulin resistance. 53 Whether this heritability depends on obesity is unclear. Insulin, like other hormones, exerts its effects by binding to specific cell surface receptors, initiating a cascade of intracellular reactions that ultimately lead to changes in glucose transport, glycogen and lipid synthesis, and gene expression (Figure 1). 55 Genetic mutations in the insulin receptor have been identified, but these are rare causes of diabetes. 44,56 Because type 2 diabetes is a polygenic disorder, inheritable influences on type 2 diabetes are likely to involve alterations of several genes. 15 To date, no genetic defect has been found in patients with typical type 2 diabetes that might cause their diabetes to be due solely to insulin resistance. 57 Initial reports of polymorphisms involving calpain-10 and the peroxisome proliferator activated receptor γ2 Pro12Ala had suggested that these may, respectively, increase and decrease the risk for developing type 2 diabetes by modifying insulin sensitivity. 58,59 However, subsequent studies suggested an overall small effect on the risk for type 2 diabetes, inconsistent results across different ethnic groups, and, more importantly, that alterations in β-cell function rather than insulin sensitivity may be involved. 57,60,61 Environmental Factors: Focus on Obesity. Intraabdominal obesity, a consequence of a modern high-fat, high-energy diet and sedentary lifestyle, is strongly correlated with insulin resistance. 35,62-64 Central adiposity appears to be a major determinant of insulin resistance not only in obese individuals but also in apparently healthy nonobese individuals who have evidence of increased abdominal fat. 65,66 In obese patients with type 2 diabetes, weight loss has been shown to normalize insulin sensitivity completely, 67,68 increase insulin-stimulated glycogen synthase activity, 67 and reverse defective insulin receptor kinase activity. 69 Moreover, it can prevent the progression to type 2 diabetes in high-risk populations, including patients

4 450 Insulin Resistance and Secretion in Type 2 Diabetes Mayo Clin Proc, April 2003, Vol 78 more in obese individuals with type 2 diabetes. Moreover, inverse correlations have been found with plasma triglycerides, postprandial plasma glucose levels, and insulin sensitivity. 77,78 Weight loss and treatment with thiazolidinediones increased plasma adiponectin in animals 79 and humans. 80 Administration of adiponectin to obese or diabetic mice reduces food intake, tissue triglycerides, and plasma glucose levels, while it increases insulin sensitivity and muscle FFA oxidation. 79,81,82 Furthermore, evidence shows that adiponectin may have antiatherogenic properties, 76 thus providing a link between obesity, insulin resistance, and cardiovascular disease. 83 Several acquired factors for the development of insulin resistance among nondiabetic, nonobese individuals have been identified, including decreased physical activity, 84 high-fat diets, 85 medications (eg, thiazide diuretics, protease inhibitors, corticosteroids, niacin), 86 and glucose toxicity. 87 Figure 1. Insulin signaling pathways. Tyrosine kinase activity of the insulin receptor phosphorylates the insulin receptor substrate (IRS) proteins IRS-1 and IRS-2, triggering a cascade of intracellular reactions, including the activation of phosphatidylinositol 3 (PI 3)-kinase and the Ras-MAPK pathway. Reprinted from Alper 55 with permission. Copyright 2000, American Association for the Advancement of Science. with prediabetes (formerly called impaired glucose tolerance) These observations suggest that most of the insulin resistance found in people with type 2 diabetes is not the result of diabetes-specific genes but rather is simply due to obesity. Although the precise mechanism underlying the relationship between abdominal obesity and insulin resistance is still uncertain, FFAs are thought to play a central role. 62,74 Abdominal adipocytes, which are inherently more resistant to the antilipolytic actions of insulin than are adipocytes in the remainder of body fat, can release excessive amounts of FFAs into the portal circulation, inducing hepatic insulin resistance and overproduction of glucose. 62 The recently identified peptide hormone resistin (signifying insulin resistance) may represent a link between obesity and type 2 diabetes. 75 Administration of antiresistin antibody was shown to improve blood glucose and the action of insulin in obese mice, whereas administration of recombinant resistin to normal mice affected both factors negatively. 75 Another potentially important factor is adiponectin (formerly called adipocyte complement-related protein of 30 kda). 76 This is a collagen-like protein related to C1qA, B, and C components of the complement system. Its expression is reduced in obese mice (OB/OB and db/db). Plasma levels are reduced in obese humans and are reduced even ROLE OF IMPAIRED INSULIN SECRETION IN TYPE 2 DIABETES MELLITUS The vast majority of patients with type 2 diabetes exhibit some degree of insulin resistance, but type 2 diabetes can occur in the absence of insulin resistance. 20,22,65,88-92 Furthermore, most obese individuals who are insulin resistant do not develop type 2 diabetes. 12,93 These individuals remain normoglycemic because they compensate for the reduction in insulin sensitivity by increasing their insulin secretion. 24,93-95 Therefore, insulin resistance per se is an insufficient cause of type 2 diabetes; the development of type 2 diabetes must involve a defect at the level of the β cell that prevents this compensatory mechanism. 95,96 Normally, insulin secretion in response to glucose is biphasic, with an early first-phase burst followed by a second, sustained phase (Figure 2). 15,97,98 Because insulin secretion is also a function of the degree of insulin resistance, some investigators use the product of an insulin sensitivity index and the insulin response to compare the appropriateness of β-cell function in individuals with different degrees of insulin sensitivity. 28, Studies of insulin responses in patients with type 2 diabetes and in those at high risk based on glucose challenge paradigms have documented various abnormalities in insulin secretion. For example, early (ie, 30 minutes) insulin responses during the oral glucose tolerance test 23,95,96 and first-phase insulin responses during intravenous infusions of glucose, 23,24 or hyperglycemic clamp experiments, 25 are reduced. In 1987, Nesher et al 22 reported that the degree of peripheral insulin resistance was similar between obese patients with diabetes or normal glucose tolerance; however, insulin secretion, as estimated by pancreatic responsiveness scores, was reduced by more than 80% in both lean and obese patients with type 2 diabetes.

5 Mayo Clin Proc, April 2003, Vol 78 Insulin Resistance and Secretion in Type 2 Diabetes 451 There is mounting evidence that insulin-secretory defects are the dominant problem among nonobese patients with diabetes. For example, in a study of elderly men with diabetes, those who were lean exhibited only an insulinsecretory defect; in contrast, their obese counterparts displayed evidence of impaired insulin secretion and insulin resistance. 20 In a recent study by Pigon et al, 23 nonobese patients with type 2 diabetes had profound impairment in the secretion of insulin, a slight reduction in extrahepatic insulin sensitivity, and no evidence of impaired hepatic insulin sensitivity. Overall, the demonstration of β-cell dysfunction before the onset of type 2 diabetes, as well as the recognition of the confounding effect of obesity on insulin sensitivity, questioned the theory that insulin resistance is the primary cause of type 2 diabetes. To clarify further the relative contribution of these 2 abnormalities at different stages in the pathogenesis of type 2 diabetes, investigators have performed studies of the insulin-secretory capacity of glucose-tolerant individuals with a predisposing ethnicity or a family history of type 2 diabetes. 21,25-34 These studies (Table 4) show that β-cell dysfunction, like insulin resistance, occurs in genetically predisposed individuals with normal glucose tolerance well before the emergence of overt diabetes. 21,25-34 For example, Pimenta et al 32 showed that both first- and second-phase insulin release, as assessed by hyperglycemic clamps, were significantly reduced among Caucasian first-degree relatives of patients with type 2 diabetes who had no insulin resistance compared with age-, sex-, and weight-matched controls. Interestingly, some of these individuals had impairments in both phases of insulin secretion, whereas others exhibited only first- or second-phase deficits. 32 These results were confirmed in a subsequent study by van Haeften et al, 33 who showed that second-phase insulin release (also assessed by hyperglycemic glucose clamps) was decreased among 21 Caucasian glucose-tolerant offspring of patients with type 2 diabetes compared with a well-matched control group. Of note, in both these studies, there were no significant differences with respect to insulin sensitivity between the predisposed subjects and the control groups (comprised of glucosetolerant subjects with no family history of type 2 diabetes), 32,33 suggesting that alterations in insulin secretion precede insulin resistance in patients at risk for developing type 2 diabetes. In recent years, compelling evidence that impaired insulin secretion is the major genetic trait has been provided via the assessment of the degree of β-cell compensation to reduced insulin sensitivity among normal glucose-tolerant offspring or siblings of Caucasian familial type 2 diabetic kindreds (ie, families with at least 2 siblings diagnosed with type 2 diabetes before age 65 years). 27,28 For example, Insulin (ng/ml) Glucose Period of glucose infusion Insulin Minutes 150 Figure 2. Multiphasic insulin release in response to glucose. A glucose stimulus (in this case, to the isolated perfused pancreas) triggers an initial burst of insulin, followed by a second slow latephase increase. Reproduced from Karam and Forsham 97 with permission from The McGraw-Hill Companies. glucose-tolerant members of Caucasian familial type 2 diabetic kindreds (but not similarly obese control subjects) exhibit impairment in β-cell compensation for obesityrelated insulin resistance. 27 Furthermore, the heritability of insulin secretion is 67%. 27,103 Specific causes of β-cell dysfunction in patients with type 2 diabetes may include (1) an initial decrease in β-cell mass, (2) increased apoptosis/decreased regeneration, (3) long-standing insulin resistance leading to β-cell exhaustion, (4) glucose toxicity-induced β-cell desensitization, (5) lipid toxicity to β cells, and (6) amyloid deposition or other conditions with the ability to reduce β-cell mass. 52 Overall, despite numerous animal and human studies that seek to elucidate the causes of β-cell dysfunction, the clinical relevance of each of these factors is not well established. Readers interested in a comprehensive review of the potential causes of β-cell dysfunction should refer to a recently published review. 52 According to data from the UKPDS, β-cell function was reduced 50% at diagnosis of type 2 diabetes, and its progressive decrease profoundly influenced the subsequent response to treatment. 104 Only 45% of patients who initially achieved hemoglobin A 1c levels lower than 7.0% still had hemoglobin A 1c levels lower than 7.0% at 6 years; this was solely due to progressive deterioration in β-cell function since insulin sensitivity did not change. 104 Similar results were observed for diet treatment failures in the Belfast study. 105 Overall, the results of case-control and prospective cohort studies suggest that, far from playing a secondary role to insulin resistance, insulin deficiency makes a critical Glucose (mg/dl)

6 452 Insulin Resistance and Secretion in Type 2 Diabetes Mayo Clin Proc, April 2003, Vol 78 Table 4. Summary of Findings From Selected Studies of Insulin Secretion in High-Risk Populations* Reference Population Glycemic status Key findings Weyer et al, Pima Indians NGT or IGT At follow-up of 4.4 and 5.5 y, 31% of NGT subjects progressed to IGT and 44% of IGT subjects progressed to type 2 diabetes, respectively Low insulin-stimulated glucose disposal and low AIR were independent predictors of progression from NGT to IGT and IGT to diabetes Elbein et al, members of 26 families NGT or IGT Body mass index was a significant predictor of S I, AIR, and with a sibling pair with type 2 diabetes DI (DI = S I AIR); when normoglycemic grouped as lean, moderately obese, and very obese, S I decreased and AIR increased with obesity; DI also decreased, indicating insufficient compensation for insulin resistance of obesity Elbein et al, members of 26 families NGT or IGT Product of S I and AIR, a measure of β-cell compensation, with a sibling pair with reduced in both groups of family members type 2 diabetes Heritability of S I AIR = 67%-70% Heritability of S I alone = 38% Heritability of AIR alone = 38% Genetic locus for type 2 diabetes may be β-cell compensatory reserve Boden et al, African American first-degree NGT During 48-h glucose infusion, controls showed well-defined relatives of patients with circadian cycles of insulin release type 2 diabetes In relatives, circadian cycles replaced with irregular, short cycles with no defined periodicity; as a result, relatives could not maintain compensation for >18 h van Haeften et al, First-degree relatives of NGT First-phase insulin release unaltered; second-phase insulin patients with type 2 diabetes release decreased; 60-, 90-, and 120-minute log plasma insulin levels correlated with second-phase insulin release Henriksen et al, First-degree relatives of NGT with insulin 7 of 20 relatives had elevated 2-h plasma glucose level on patients with type 2 diabetes resistance induced OGTT during treatment; these relatives had reduction in by dexamethasone first-phase insulin secretion both before and during treatment Byrne et al, Subjects with 1 or 2 parents Five groups: normal Insulin-secretion defects in NGT and IGT included decrease with type 2 diabetes and/or controls, normo- in AIR relative to degree of insulin resistance and IGT glycemic offspring, abnormalities in response to oscillatory glucose infusion nondiagnostic OGTT, IGT, mild diabetes Haffner et al, Mexican Americans enrolled NGT or IGT Insulin resistance and insulin deficiency independent in 7 y follow-up of predictors of type 2 diabetes San Antonio Heart Study Pimenta et al, First-degree relatives of NGT First- and/or second-phase insulin responses reduced; patients with type 2 diabetes insulin sensitivity comparable between study and control groups Vaag et al, Identical twin pairs discordant NGT or IGT Both groups of nondiabetic twins were insulin resistant and for type 2 diabetes exhibited reductions in first-phase insulin release and maximum insulin-secretory capacity Eriksson et al, First-degree relatives of NGT or IGT First-phase insulin-secretory response absent in patients patients with type 2 diabetes with type 2 diabetes and impaired in relatives with IGT *AIR = acute insulin response; DI = disposition index; IGT = impaired glucose tolerance; NGT = normal glucose tolerance; OGTT = oral glucose tolerance test; S I = insulin sensitivity. contribution to the pathogenesis of type 2 diabetes at every stage in the natural history of the disease. TYPE 2 DIABETES MELLITUS AS A HETEROGENEOUS DISORDER: IMPLICATIONS FOR TREATMENT Although impaired insulin secretion and insulin resistance have both been proposed as the primary pathophysiologic defect in type 2 diabetes, at the present time the body of literature suggests that these 2 phenomena should be considered interrelated elements rather than competing explanations. Both defects are logical therapeutic targets. Therefore, optimal management of type 2 diabetes demands an individualized approach to treatment that considers the heterogeneous nature of this disorder and

7 Mayo Clin Proc, April 2003, Vol 78 Insulin Resistance and Secretion in Type 2 Diabetes 453 that addresses both insulin-resistance and insulin-secretory defects. Recent long-term studies, particularly the DCCT and UKPDS, showed the need for effective glycemic control to prevent the complications of type 1 and type 2 diabetes. 5-7,106 Cost-effectiveness analyses of the UKPDS indicate that the increased cost of intensive treatment is offset by the substantial reduction in the cost of diabetes-related complications and the increase in time free of complications. 107 It appears that more strict glycemic control (and better management of hypertension and lipid abnormalities) is needed to reduce the risk of macrovascular disease compared with microvascular disease A goal of a postprandial plasma glucose level lower than 140 mg/dl may be more appropriate. 112 Early-stage type 2 diabetes and prediabetes are associated with impaired early insulin release after glucose ingestion, whereas late (eg, 120 minutes) plasma insulin levels may be increased due to late hyperglycemia. 96, Both animal and human data suggest that first-phase insulin release is a key mediator of hepatic glucose production, thereby establishing a link between first-phase insulin release and postprandial hyperglycemia in patients with type 2 diabetes. 116 Bruce et al 117 showed that administering insulin at mealtime significantly improved postprandial glucose levels compared with an equivalent insulin dosage given 30 minutes later. From a therapeutic standpoint, early insulin release capacity can be either restimulated with a secretagogue or replaced completely with fast-acting insulin. However, patients with type 2 diabetes who exhibit reduced insufficient late insulin responses may require a long-acting insulin preparation to replace physiologic β- cell function. Diet and exercise, which have been shown to attenuate insulin resistance, remain the cornerstone of type 2 diabetes management. 2 As shown by the UKPDS, 118 however, these lifestyle interventions are generally insufficient on a long-term basis for achieving and maintaining optimal levels of glycemic control. 2 Early and aggressive pharmacological therapy is usually needed. Over time, the proportion of patients who maintain acceptable glycemic control while taking oral agents alone or in combination decreases such that a considerable proportion of patients require insulin therapy. 119 The progressive deterioration in β-cell function appears to be largely responsible for this lack of efficacy with oral therapies over time. Conceivably, early initiation of regimens that combine one or more agents with different mechanisms (eg, an oral secretagogue and sensitizer) may provide better long-term glycemic control than a single agent. Earlier use of insulin is also indicated a rational approach given the awareness that β-cell deterioration occurs early in the disease process. The sulfonylureas (eg, glyburide, glipizide, glimepiride), the most widely prescribed class of oral hypoglycemic agents, primarily exert their glucose-lowering effects by stimulating the release of insulin from β cells. The meglitinides (eg, repaglinide) and the D-phenylalanine analogue nateglinide, which are not chemically related to the sulfonylureas, also enhance β-cell insulin secretion. Other newer classes of oral agents, the thiazolidinediones (eg, rosiglitazone, pioglitazone) and biguanides (eg, metformin), act by lowering insulin resistance rather than stimulating insulin secretion. The availability of a broad range of oral hypoglycemic agents and multiple insulin preparations with varying onsets and durations of action facilitates the design of individualized treatment regimens for type 2 diabetes. These treatment regimens are discussed in detail in the other 2 reviews on diabetes published in this issue. 120,121 After decades of debate, current opinion favors the idea that type 2 diabetes is the result of a genetic β-cell defect that limits compensation for, in most instances, obesityinduced insulin resistance. 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