114 Schneider and Sobel when symptomatic coronary artery disease is present. Beneficial effects of glyco- protein IIb/IIIa inhibitors are striking in diabetic subjects who require percutane- ous coronary interventions (PCI). Analysis of results in diabetic subjects with acute coronary syndromes demonstrates that treatment of diabetic patients with acute coronary syndromes undergoing PCI with tirofiban reduces the 30-day inci- dence of death or myocardial infarction from 15.5 to 4.7%. Similarly, treatment with abciximab during elective percutaneous coronary intervention reduces the mortality rate after 1 year from 4.5 to 2.5%. Accordingly, GP IIb/IIIa inhibitors should be used aggressively in the treatment of diabetic subjects with acute coro- nary syndromes (unstable angina and non-ST-elevation myocardial infarction) and uniformly in association with percutaneous coronary intervention. As noted above, hypertension should be treated vigorously, generally with ACE inhibitors, because of their demonstrated renal protective effects and nor- malization of the imbalance in the fibrinolytic system of diabetic subjects. Treat- ment with ACE-inhibitors is associated with a reduced rate of recurrent coronary thrombosis. Results both in vitro and in vivo demonstrate that ACE inhibition, by decreasing formation of angiotensin-II and angiotensin-IV, decreases expres- sion of PAI-1. Thus, ACE-inhibitor therapy is likely to reduce cardiovascular events through diverse mechanisms, including its effect on the decreased fibrino- lytic capacity in diabetes. VI. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE Subjects with diabetes mellitus have a high prevalence and rapid progression of cardiovascular, peripheral vascular, and cerebral vascular disease secondary and in part attributable to: (1) increased platelet reactivity; (2) increased prothrom- botic activity reflecting increased concentrations and activity of coagulation fac- tors and decreased activity of antithrombotic factors; and (3) decreased fibrino- lytic system capacity resulting from overexpression of PAI-1 by hepatic, arterial, and adipose tissue in response to hyperinsulinemia, hypertriglyceridemia, and hyperglycemia. The macrovascular disease appears to be accelerated by an insulin-dependent imbalance between concentrations of plasminogen activators and PAI-1 in blood and in vessel walls. Therapy designed to reduce insulin resis- tance decreases concentrations in blood not only of insulin but also of PAI-1. Thus, the treatment of subjects with diabetes, and particularly type 2 diabetes, should be designed to achieve stringent metabolic control while at the same time reducing insulin resistance and hyperinsulinemia. Treatment designed to attenu- ate both the hormonal and metabolic abnormalities is likely to reduce hyperactiv- ity of platelets, decrease the intensity of the prothrombotic state, and normalize activity of the fibrinolytic system in blood and in vessel walls, thereby reducing the rate of progression of macrovascular disease and its sequelae. Coagulation and Fibrinolytic Systems 115 SUGGESTED READING 1. Jones RL. Fibrinopeptide-A in diabetes mellitus. Relation to levels of blood glucose, fibrinogen disappearance, and hemodynamic changes. Diabetes 1985; 34:836–843. 2. Mansfield MW, Heywood DM, Grant PJ. Circulating levels of factor VII, fibrinogen, and von Willebrand factor and features of insulin resistance in first-degree relatives of patients with NIDDM. Circulation 1996; 94:2171–2176. 3. Lupu C, Calb M, Ionescu M, Lupu F. Enhanced prothrombin and intrinsic factor X activation on blood platelets from diabetic patients. Thromb Haemost 1993; 70:579– 583. 4. McGill JB, Schneider DJ, Arfken CL, Lucore CL, Sobel BE. Factors responsible for impaired fibrinolysis in obese subjects and NIDDM patients. Diabetes 1994; 43:104– 109. 5. Sobel BE. Increased plasminogen activator inhibitor-1 and vasculopathy. A reconcil- able paradox. Circulation 1999; 99:2496–2498. 6. Calles-Escandon J, Mirza S, Sobel BE, Schneider DJ. Induction of hyperinsulinemia combined with hyperglycemia and hypertriglyceridemia increases plasminogen acti- vator inhibitor type-1 (PAI-1) in blood in normal human subjects. Diabetes 1998; 47: 290–293. 7. Theroux P, Alexander J Jr, Pharand C, Barr E, Snapinn S, Ghannam AF, Sax FL. Glycoprotein IIb/IIIa receptor blockade improves outcomes in diabetic patients pre- senting with unstable angina/non-ST-elevation myocardial infarction: results from the platelet receptor inhibition in ischemic syndrome management in patients limited by unstable signs and symptoms (PRISM-PLUS) study. Circulation 2000; 102:2466– 2472. 8. Bhatt DL, Marso SP, Lincoff AM, Wolski KE, Ellis SG, Topol EJ. Abciximab reduces mortality in diabetics following percutaneous coronary intervention. J Am Coll Cardiol 2000; 35:922–928. 9. Ridker PM, Vaughan DE. Potential antithrombotic and fibrinolytic properties of the angiotensin converting enzyme inhibitors. J Thromb Thrombolysis 1995; 1:251–257. 7 Insulin Resistance, Compensatory Hyperinsulinemia, and Coronary Heart Disease: Syndrome X Gerald M. Reaven Stanford University School of Medicine, Stanford, California I. INTRODUCTION The goal of this chapter will be to provide evidence for the importance of insulin resistance and compensatory hyperinsulinemia, and the manifestations of insulin resistance/compensatory hyperinsulinemia (syndrome X), in the genesis of coro- nary heart disease (CHD) in nondiabetic individuals. Although insulin resistance, and the body’s response to this defect, are central to the development of CHD in patients with type 2 diabetes, the pathophysiological characteristics of type 2 diabetes and syndrome X are sufficiently different so as to preclude a thoughtful discussion of both syndromes within the constraints of this chapter. On the other hand, discussion of the relationship between insulin resistance, compensatory hyperinsulinemia, and CHD in those with syndrome X will be of considerable relevance to patients with type 2 diabetes. II. WHAT IS INSULIN RESISTANCE? The ability of insulin to stimulate muscle glucose disposal varies approximately tenfold in the population at large. Insulin-resistant individuals develop type 2 diabetes when they can no longer secrete enough insulin to maintain the degree of compensatory hyperinsulinemia necessary to maintain euglycemia. However, the vast majority of individuals that demonstrate muscle insulin resistance are 117 118 Reaven able to sustain the magnitude of compensatory hyperinsulinemia needed to pre- vent gross decompensation of glucose tolerance. As commonly used, the phrase ‘‘insulin resistance’’ refers to a decrease in the ability of a defined amount of insulin to stimulate glucose disposal by muscle. However, there is no accepted criterion that permits a precise definition of the magnitude of the defect in insulin-stimulated glucose disposal by muscle that provides the means to designate a person as ‘‘insulin sensitive’’ or ‘‘insulin resis- tant.’’ Instead, as shown in Figure 1, insulin-stimulated glucose disposal rates in nondiabetic individuals vary continuously from the most insulin-sensitive to the most insulin-resistant individual, and the best we can do is to understand that the more insulin-resistant an individual, the more at risk they are of developing one or more of the manifestations of syndrome X. The variability of insulin- stimulated glucose disposal is 490 healthy volunteers is shown in Figure 1. These measurements were made with the insulin suppression test, an approach to quan- tify insulin-mediated glucose disposal by determining the steady-state plasma insulin (SSPI) and steady-state plasma glucose (SSPG) concentrations achieved during the last 30 min of a continuous infusion of octreotide, insulin, and glucose. The octreotide infusion suppresses endogenous insulin secretion, and the exoge- nous insulin infusion produces a steady-state level of physiological hyperinsuli- nemia. Because the SSPI concentration is similar for all subjects, the SSPG con- centration provides a direct measure of the ability of insulin to mediate disposal of an infused glucose load; the higher the SSPG concentration, the more insulin resistant the individual. Figure 1 SSPG concentrations of 490 volunteers divided into deciles. The mean (ϮSEM) SSPG, SSPI, and fasting (F) insulin concentration of each decile are shown below each bar. (Reproduced from Ref. 20 with permission of the author and publisher.) Syndrome X 119 Each of the bars in Figure 1 represents the mean SSPG concentration for 49 individuals. It is apparent that there is an enormous spread of SSPG concentra- tions in the 490 volunteers (i.e., the degree of insulin resistance varies dramati- cally in the population at large). Indeed, there is an approximate tenfold difference between the most insulin-sensitive and insulin-resistant individuals. It should also be noted from Figure 1 that the fasting (F) insulin concentrations increase in parallel with the SSPG concentrations. Based upon the results of prospective studies, it has been estimated that the upper 25 to 33% of the nondiabetic population (i.e., the upper three deciles in terms of SSPG concentration) are at greatly increased risk of presenting with one or more of the manifestations of syndrome X. If 25 to 33% of the population at large is sufficiently insulin resistant to be at increased risk of syndrome X and/or type 2 diabetes, it is of obvious interest to know what determines the ability of insulin to stimulate muscle glucose dis- posal. At one level, this question is easy to answer. Differences in degree of obesity and physical activity are the two most important lifestyle variables that modulate insulin action, and they explain approximately 25% each of the varia- tions in insulin action from person to person. By inference, it can then be argued that differences in genetic background account for the remaining 50% of the variability in insulin resistance. Although the actual numerical values may not be entirely accurate, they represent reasonable approximations. The crucial thing to remember is that variations in body weight and level of physical activity are modulators of insulin action; they are not the primary cause of insulin resistance. A second point that must be appreciated is that although the ability of insu- lin to mediate glucose disposal by muscle is the conventional way of assessing insulin resistance, adipose tissue appears to be as resistant to regulation by insulin as muscle. The belated recognition of adipose tissue insulin resistance is easily understood if both the techniques usually used to assess resistance to insulin- mediated glucose disposal and the differences in the dose-response characteristics of insulin action on adipose tissue versus muscle are taken into account. For example, a plasma insulin concentration of ϳ20 µU/mL will suppress by approxi- mately 50% the release of free fatty acids (FFA) by adipose tissue; a circulating insulin concentration that has relatively little effect on stimulating glucose dis- posal by muscle. The infusion techniques conventionally used to quantify insulin resistance (i.e., the ability of insulin to stimulate glucose disposal by muscle) are almost uniformly performed by maintaining steady-state plasma insulin concen- trations at least fourfold greater than the level needed to half-maximally suppress adipose tissue lipolysis. As a result, plasma FFA levels are maximally suppressed in all subjects, and differences in adipose tissue resistance to insulin cannot be discerned. It is now clear that the degree of insulin resistance in muscle and in adipose tissue is highly correlated, and that both defects contribute to the manifes- tations of syndrome X. 120 Reaven If not for this difference in tissue dose-response curve, the increase in plasma FFA concentrations would be proportionate to the degree of hyperinsuli- nemia in subjects with syndrome X. However, because of the enhanced sensitivity of the adipose tissue to insulin, plasma FFA concentrations are only marginally increased as long as hyperinsulinemia is maintained. On the other hand, the fact that there is a less dramatic increase in plasma FFA concentration should not obscure the fact that adipose tissue insulin resistance contributes substantially to the development of syndrome X. Although attention has been focused on the parallel abnormalities that exist in muscle and adipose tissue to their regulation by insulin, it is important to understand that many of the manifestations of syndrome X are due to the effects of the compensatory hyperinsulinemia on tissues that remain insulin sensitive, despite the presence of muscle and adipose tissue insulin resistance in the same individual. There are several examples of this phenomenon. For example, there is evidence that the sympathetic nervous system (SNS) remains normally respon- sive to insulin stimulation in individuals with muscle insulin resistance. Thus, the compensatory hyperinsulinemia present in insulin-resistant individuals leads to enhanced SNS activity and a series of changes that helps explain why insulin- resistant/hyperinsulinemic individuals are at increased risk to develop hyperten- sion. There is also substantial evidence that the liver does not share in the insulin resistance present in muscle and adipose tissue. For example, muscle insulin resis- tance leads to higher insulin levels (to prevent the development of type 2 diabe- tes), and higher FFA concentrations occur because of adipose tissue insulin resis- tance. In contrast, the liver is functionally normal, and its response to the higher insulin and FFA levels is to enhance its synthesis and secretion of triglyceride (TG)-rich lipoproteins, leading to hypertriglyceridemia. Another major organ that retains normal insulin sensitivity, despite muscle and adipose tissue insulin resistance, is the kidney, and there are two features of syndrome X that are likely to be dependent on the retention of normal insulin action on the kidney—hyperuricemia and salt-sensitive hypertension—both of which will be discussed in greater detail subsequently. III. WHY IS INSULIN RESISTANCE IMPORTANT? As shown in Figure 2, insulin-resistant individuals are at increased risk of devel- oping either type 2 diabetes or one or more of the cluster of abnormalities sub- sumed under the general heading of syndrome X. Although these two syndromes have been separated for pedagogic purposes, it should be emphasized that they share many attributes not the least of which is increased risk of CHD, and that a finite proportion of individuals initially designated as syndrome X will eventually develop type 2 diabetes. Syndrome X 121 Figure 2 A schematic description of the relationship between insulin resistance, insulin secretory response, type 2 diabetes, and syndrome X and coronary heart disease (CHD). The relationship between insulin resistance and type 2 diabetes has been defined as the consequence of multiple prospective, population-based studies published over the past 30 years. There seems to be little doubt that insulin resis- tance and/or hyperinsulinemia (a surrogate measure of insulin resistance in non- diabetic individuals) are the most powerful predictors of the development of type 2 diabetes. The role of an impairment of insulin secretory function is less well understood, and the phrase ‘‘inadequate insulin secretion,’’ as seen in Figure 2, is a euphemism that should not obscure the fact that absolute plasma insulin concentrations throughout the day are, on the average, higher in absolute terms in the majority of patients with type 2 diabetes as compared to normoglycemic individuals. As emphasized earlier, most insulin-resistant individuals remain in the right limb of Figure 2; they secrete enough insulin to avoid becoming sufficiently hy- perglycemic to merit the diagnosis of type 2 diabetes. However, this victory is a hollow one, and in 1988 a relationship between insulin resistance, compensatory hyperinsulinemia, and a cluster of related abnormalities, all of which increase risk of CHD, was identified and designated as syndrome X. In the remainder of this section, the evidence linking insulin resistance and compensatory hyperinsul- inemia to all the abnormalities now presumed to comprise syndrome X will be reviewed (Table 1). A. Glucose Metabolism Within the population satisfying the criteria for normal glucose tolerance, the greater their degree of insulin resistance, the higher their plasma glucose concen- tration. In a smaller subset of insulin-resistant individuals, the degree of compen- satory hyperinsulinemia is not sufficient to maintain normal glucose tolerance, and they are classified as having either impaired fasting glucose or impaired glu- 122 Reaven Table 1 Manifestations of Insulin Resistance/ Compensatory Hyperinsulinemia (Syndrome X) A. Glucose Metabolism 1. Impaired fasting glucose 2. Impaired glucose tolerance B. Uric Acid Metabolism 1. ↑ Plasma uric acid concentration 2. ↓ Plasma renal uric acid clearance C. Dyslipidemia 1. ↑ Triglyceride concentration 2. ↑ Postprandial lipemia 3. ↓ HDL cholesterol concentration 4. ↓ LDL particle diameter D. Blood Pressure 1. ↑ Blood pressure 2. ↑ Sympathetic nervous system activity 3. ↑ Renal sodium retention E. Procoagulant Activity 1. ↑ Plasminogen activator inhibitor-1 2. ↑ Fibrinogen F. Reproductive System 1. Polycystic ovary syndrome cose tolerance. In an even smaller number of insulin-resistant individuals, insulin secretory function fails to the degree that permits manifest hyperglycemia to de- velop. Such individuals have type 2 diabetes. Syndrome X and type 2 diabetes share insulin resistance as a basic metabolic defect, but the designation of syn- drome X should be limited to individuals who have maintained sufficient insulin secretory function to remain nondiabetic. B. Uric Acid Metabolism An association between increases in plasma uric acid concentration and increased CHD risk has been known for many years. Hyperuricemia is commonly seen in individuals with glucose intolerance, dyslipidemia, and hypertension. Significant correlations exist between plasma uric acid concentration and both insulin resis- tance and the plasma insulin response to an oral glucose challenge in healthy volunteers, and individuals with asymptomatic hyperuricemia have higher plasma insulin responses to oral glucose; higher TG and lower high-density lipoprotein (HDL) cholesterol concentrations; and higher blood pressure when compared to volunteers with normal serum uric acid concentrations. Syndrome X 123 The increase in plasma uric concentrations in insulin-resistant, nondiabetic individuals appears to result from a decrease in renal uric acid clearance second- ary to the effect of compensatory hyperinsulinemia on the handling of uric acid by the kidney. This is one of several instances in which a manifestation of syn- drome X occurs because one organ system remains sensitive to insulin action, in this case the kidney, whereas the muscle in the same individual is insulin resistant. C. Dyslipidemia The most central feature of syndrome X is hypertriglyceridemia. However, there are several other abnormalities that rarely occur in the absence of an increase in plasma TG concentration and belong to the cluster of CHD risk factors that make up syndrome X. 1. Hypertriglyceridemia A direct relationship exists between insulin resistance, compensatory hyperin- sulinemia, and plasma TG concentration, and this association is seen in both hypertriglyceridemic and normotriglyceridemic subjects. Since hepatic very-low- density lipoprotein (VLDL)–TG synthesis and secretion are highly correlated with plasma VLDL–TG concentrations, it can be concluded that the more insulin resistant an individual, and the higher the resultant plasma insulin concentration, the greater will be the increase in hepatic VLDL–TG synthesis and secretion, and the more elevated the plasma TG concentration. The increase in hepatic VLDL–TG secretion in syndrome X results from the effect of the ambient hyper- insulinemia, enhancing the hepatic conversion of FFA to TG, and an increase in FFA flux to the liver as a result of resistance to the antilipolytic effect of insulin at the level of the adipose tissue. As discussed above, the liver is responding normally to the day-long hyperinsulinemia in the presence of muscle and adipose tissue insulin resistance. 2. Postprandial Lipemia Once fasting hypertriglyceridemia develops in insulin-resistant individuals, there will be an accentuation of postprandial lipemia, and the accumulation of TG- rich lipoproteins throughout the day. Both insulin resistance and compensatory hyperinsulinemia, significantly and independently, predict the postprandial accu- mulation of TG-rich lipoproteins in nondiabetic individuals. Thus, elevations in postprandial lipemia are highly correlated with insulin resistance and compensa- tory hyperinsulinemia, directly by unknown mechanisms, and indirectly by the ability of insulin resistance and/or compensatory hyperinsulinemia to stimulate hepatic VLDL–TG secretion and increase the fasting TG pool size. [...]... triglyceride-rich lipoproteins, and coronary heart disease risk Am J Cardiol 2000; 85: 45 48 20 Yeni-Komshian H, Carantoni M, Abbasi F, Reaven GM Relationship between several surrogate estimates of insulin resistance and quantification of insulin-mediated glucose disposal in 490 healthy, nondiabetic volunteers Diabetes Care 2000; 23: 171–1 75 8 Detection and Diagnosis of Syndromes of Insulin Resistance and of Diabetes. .. reduce many features of the syndrome and should be a fundamental part of the treatment program Previous studies in China (50 ) and in Finland (51 ) have demonstrated that the incidence of progression from IGT to overt diabetes is significantly reduced by relatively modest decreases in body weight and increased physical activity and the recent announcement of the results of the NIH-sponsored Diabetes Prevention... cardiovascular disease A cluster of biochemical abnormalities is frequently associated with insulin resistance syndrome These include a characteristic dyslipidemia consisting of elevated serum triglycerides and very-low-density lipoproteins (VLDL), a decrease in high-density-lipoprotein cholesterol (HDL-C), and a pattern of small, dense, low-density-lipoprotein (LDL) particles (31–34) Serum uric acid is often... concentration of 126 mg/dL and the 2-h OGTT value of 200 mg/dL and both of these levels correlate well with the appearance of microvascular complications of diabetes including retinopathy, nephropathy, and neuropathy It is also recognized that IFG and IGT are both conditions that are associated with an increased risk of developing overt type 2 diabetes mellitus and an increased risk for cardiovascular disease. .. apoprotein A-1 4 Low-Density-Lipoprotein Particle Diameter LDL particle size in most individuals can be characterized by a predominance ˚ ˚ of either larger LDL (diameter Ͼ 255 A, pattern A) or smaller LDL (Յ 255 A, pattern B) particles Individuals with pattern B have higher plasma TG and lower HDL cholesterol concentrations, and are at increased risk of CHD Healthy volunteers with small, dense LDL particles... looked for in women with a history of gestational diabetes mellitus (GDM) or PCOS and members of various ethnic and racial groups that have increased risk for obesity and type 2 diabetes One of the most common manifestations of insulin resistance syndrome is the combination of obesity and type 2 diabetes mellitus In the United States, approximately 80% of people with type 2 diabetes mellitus are overweight,... constitute the clinical condition of insulin resistance These effects are mediated by a cascade of phosphorylation reactions involving the insulin receptor, insulin receptor substrates (IRS-1 and IRS-2), and activation of the phosphoinositol 3′ kinase (PI-3′-K) pathway On the other hand, cell growth and differentiation are regulated primarily by the SHC, GRB-2, and the MAP-kinase pathways, which may or... accelerated atherosclerosis Coronary artery disease and other macrovascular diseases are the major cause of mortality and morbidity in patients with insulin resistance syndrome, and cardiovascular risk reduction should be a major goal of therapy Screening for and aggressive management of all aspects of insulin resistance syndrome are critical to reducing long-term micro- and macrovascular complications Recent... maintenance of a normal fasting blood glucose concentration but a value that is intermediate between normal and the diabetic range 2 h after a 7 5- g oral glucose load With further impairment of beta-cell function, both fasting and postprandial blood glucose concentrations increase and overt diabetes mellitus develops This sequence of events has been demonstrated in prospective studies of insulin resistance and. .. fasting and 120 min after a 7 5- g glucose challenge; (2) lipid and lipoprotein concentrations; and (3) blood pressure provide Syndrome X 131 Table 2 Diagnosis of Syndrome X Variable Glucose (fasting) Glucose (120 min) Triglyceride HDL cholesterol Men Women Blood pressure Unlikely Likely Ͻ90 mg/dL Ͻ140 mg/dL Ͻ1 25 mg/dL Ͼ1 05 Ͻ126 mg/dL 140–200 mg/dL Ͼ200 mg/dL Ͼ 45 mg/dL 55 mg/dL Ͻ130/80 mm/Hg Ͻ 35 mg/dL Ͻ45 . Results both in vitro and in vivo demonstrate that ACE inhibition, by decreasing formation of angiotensin-II and angiotensin-IV, decreases expres- sion of PAI-1. Thus, ACE-inhibitor therapy is. activity of coagulation fac- tors and decreased activity of antithrombotic factors; and (3) decreased fibrino- lytic system capacity resulting from overexpression of PAI-1 by hepatic, arterial, and. reduce insulin resis- tance decreases concentrations in blood not only of insulin but also of PAI-1. Thus, the treatment of subjects with diabetes, and particularly type 2 diabetes, should be