Medical Management of Diabetes and Heart Disease - part 2 pps

Types of Diabetes 21 higher in the women than in the normal population. Their data indicated that the insulin resistance syndrome preceded the development of type 2 diabetes by many years and that impaired glucose tolerance was associated with the insulin resistance syndrome. Recently, they have further analyzed their prediabetic cohort by defining insulin resistance at baseline by the HOMA model and insulin secretion by the incremental increase in plasma insulin 30 min after an oral glucose load divided by the incremental increase in plasma glucose. Of 195 individuals who developed diabetes, 161 were insulin resistant at baseline and 34 were insulin sensitive. The components of the insulin resistance syndrome were present only in those with insulin resistance as determined by HOMA (36). Insulin resistance occurs very commonly in societies that have acquired western cultural patterns. In Europe, it is estimated that 16% of the adult population has the insulin resistance syndrome. In a recent analysis of the Botnia population in Finland, the prevalence of the metabolic syndrome as defined by WHO was assessed in individuals with normal glucose tolerance, impaired glucose tolerance, or impaired fasting plasma glucose (IFG), and type 2 diabetes (37). The WHO definition of the metabolic syndrome is (1) hypertension (BP Ͼ160/90 mmHg or treatment for hypertension); (2) dyslipidemia, defined as plasma triglyceride Ն1.7 mmol/L (150 mg/dL) and/or HDL cholesterol Ͻ0.9 mmol/L (35 mg/dL) in men or Ͻ1.0 mmol/L (38.5 mg/dL) in women; (3) obesity, defined as BMI Ն30 kg/m 2 and/or WHR Ͼ0.90 in men or Ͼ0.85 in women; and (4) microalbuminuria (urinary albumin excretion Ն20 µg/min). Fifteen (10%) of normal glucose-tolerant men and women aged 35 to 70 years had the metabolic syndrome as compared to 64 (42%) of those with IFG/IGT and 84 (78%) of those with type 2 diabetes. A routine health examination of 2113 middle-aged men and women in Tokyo in the early 1990s revealed the following prevalence of components of the insulin resistance syndrome: obesity 20.9%; hypertension 23.1%; hyperinsulinemia 11.0%; hypertriglyceridemia 24.4%; low HDL cholesterol 23.0% (38). The individuals with hyperinsulinemia had higher plasma triglycerides, lower plasma HDL cholesterol, higher systolic and diastolic blood pressure, and higher area- under-the-plasma glucose curve during the oral glucose tolerance than those with normoinsulinemia matched for age, sex, and BMI. Individuals with glucose intolerance (defined as 2-h plasma glucose Ն133 mg/dL after a 100-g oral glucose load) had higher plasma triglycerides, higher systolic and diastolic blood pres- sures, and higher area-under-the-2-h plasma glucose curve during the OGTT as compared to the normal glucose-tolerant individuals matched for age, sex, and BMI. As noted previously, fasting plasma glucose as well as post-glucose-challenge plasma glucose predicts the future development of type 2 diabetes. This was the reason for the definition of the new category of glucose intolerance called 22 Lebovitz impaired fasting glucose. IFG is defined as a fasting plasma glucose Ն110 mg/ dL (6.2 mmol/dL) and Ͻ126 mg/dL (7.0 mmol/dL). The introduction of this category has created much controversy. Many analyses of data bases, including those in the DECODE study, have shown that IFG consists of some who would be diagnosed as type 2 diabetics by the 2-h post-glucose-challenge plasma glucose Ն200 mg/dL (11.1 mmol/L), some who have IGT, and a small subset who have only IFG (39,40). Some series show that IFG predicts CV disease while others show little or no predictive value (41). In studies where IFG predicts future CVD (as in the CARE secondary prevention study employing pravastatin in patients post myocardial infarction), the IFG cohort has the insulin resistance syndrome with increased BMI and waist circumference, increased systolic blood pressure, and the characteristic dyslipidemia (42). Insulin resistance can occur very early in life. Data from an ongoing prospective study of low-birth-weight infants in India indicate that these children can develop the insulin resistance syndrome as early as 8 years of age. Many studies have found insulin resistance in young adults who are first degree relatives of individuals who have type 2 diabetes. Insulin resistance is a characteristic of individuals who have visceral obesity. Individuals who are obese as assessed by BMI are not necessarily insulin resistant nor do they have the insulin resistance syndrome. Brochu et al. examined the metabolic characteristics of 43 obese, sed- entary, postmenopausal women (44). Despite comparable BMI (31.5 vs. 34.7 kg/ m 2 ) and fat mass (37.3 vs. 39.0 kg), 17 individuals had normal insulin sensitivity and 26 were insulin resistant as assessed by the euglycemic hyperinsulinemic clamp. The obese individuals with normal insulin sensitivity had 49% less visceral adipose tissue than the resistant individuals, and had normal fasting and post-glucose-challenge plasma glucose and insulin and mean plasma triglycerides of 1.50 mmol/L (133 mg/dL) and plasma HDL cholesterol of 1.16 mmol/L (45 mg/dL). The insulin-resistant individuals had hyperinsulinemia and the classic dyslipidemia of insulin resistance as well as borderline increases in fasting and post-glucose-challenge plasma glucose levels. The evidence suggesting that the insulin resistance syndrome plays a central role in the development of macrovascular disease in type 2 diabetic patients comes from many sources. In 1989, Banerji and Lebovitz described two variants of type 2 diabetes: one with impaired insulin action (insulin-resistance variant) and one with normal insulin action (insulin-sensitive variant) (6). Their insulin- sensitive patients had none of the components of the insulin resistance syndrome, while the insulin-resistant patients had the classic insulin resistance syndrome (17). These observations were extended by Haffner et al., who showed that insulin-sensitive type 2 diabetic patients had lower BMI and waist circumference, lower plasma triglyceride and higher plasma HDL cholesterol levels and larger, more buoyant, LDL particles, and lower plasma fibrinogen and plasminogen Types of Diabetes 23 activator inhibitor 1 (PAI-1) levels than insulin-resistant type 2 patients (45). In essence, the insulin-sensitive type 2 diabetic patients had none of the characteristics of the insulin resistance syndrome. In the United Kingdom Pro- spective Diabetes Study (UKPDS), newly diagnosed type 2 diabetic Caucasian, Asian, Indian, and Afro-Caribbean patients were randomized to either intensive or conventional glucose control treatment programs and the effects on clinical diabetic complications were assessed over a mean of 11 years. At baseline, the Afro-Caribbean population had less insulin resistance and insulin resistance components and more beta-cell deficiency than the Caucasian population (46). The relative risk of the Afro-Caribbean patients developing a fatal or nonfatal myocardial infarction over the 11-year follow-up was 0.4 that of the Caucasian population (47). Two large, long-term prospective studies from Finland have examined the relationship between the insulin resistance syndrome and the development of coronary heart events in nondiabetic men. An analysis of 22-year follow-up data from the Helsinki Policemen Study (48) showed that a factor analysis including six risk factor variables that are considered to be components of the insulin resistance syndrome (BMI, subscapular skinfold, areas under the plasma glucose and insulin curves during the oral glucose tolerance test, mean blood pressure, and plasma triglyceride) independently predict the risk of CHD (hazard ratio 1.48) and stroke (hazard ratio 2.02). A 7-year follow-up study of 1069 subjects aged 65 to 74 years from eastern Finland assessed the relationship of various clusters of risk factors to predict CHD events in men and women (49). An insulin resistance factor (BMI, WHR, fasting plasma glucose, insulin, and triglycerides) predicted CHD events in elderly men (hazard ratio 1.33), but not in elderly women. In the Botnia population, cardiovascular outcomes were assessed in 2401 subjects. The adjusted relative risk of developing CHD was 2.96 and of stroke 2.27 in those whom at baseline had the metabolic syndrome as defined by WHO. Cardiac mortality in 3606 subjects with a mean follow-up of 6.9 years was 12.0% in those who had the metabolic syndrome and 2.2% in those who did not (37). Outcome studies indicate a statistical relationship between CVD events and each of the various components of the insulin resistance syndrome (37,50–56). The extensive interrelationships among the various components of the insulin resistance syndrome (9,10,37,48) have prevented identifying with certainty whether certain independent individual components underlie the syndrome or, more importantly, whether specific major components are responsible for the accelerated atherosclerosis and increased macrovascular disease. The mechanism by which insulin resistance is created and the consequences of insulin resistance that contribute to macrovascular and perhaps mi- 24 Lebovitz crovascular disease have been the subjects of intensive investigations and numerous speculations. Considerable new data have suggested that insulin resistance and its dyslipidemia are related to the metabolic consequences of visceral adiposity (8,26,28,30,44,57). It is likely that adipose tissue releases circulating factors that both facilitate and inhibit insulin action (58–61). Free fatty acids (62) and tumor necrosis factor-α (63) inhibit insulin action by blocking activation of the insulin receptor substrate (IRS) phosphoinositide-3 kinase (PI-3 kinase) pathway. This limb of the intracellular insulin action cascade is responsible for regulating insulin’s action on glucose transport and lipid metabolism (64). The other limb of the intracellular insulin action cascade is the MAP kinase pathway, which regulates insulin’s mitogenic and growth activities (64). This pathway is not inhibited in the insulin resistance syndrome (37,65). Insulin acts on endothelial cells to regulate vascular tone and other aspects of endothelial function (66). Insulin action on endothelial cells is mediated by the intracellular IRS PI-3 kinase pathway and this action is inhibited in the insulin resistance syndrome just as are the intermediary metabolism effects (67–69). The ability of insulin to generate nitric oxide by activating endothelial cell nitric oxide syn- thase is markedly decreased (67). The result is that endothelial dysfunction is a characteristic finding in the insulin resistance syndrome (66,68–70). The distur- bance of endothelial function results in increased synthesis of growth factors and adhesion molecules, proliferation of matrix and smooth muscle cell, and increased expression of PAI-1 gene (66). Increased peripheral resistance and increases in mean arterial blood pressure are probably due in part to an imbalance of the angiotensin-2 and endothelin actions on the endothelial cells predomi- nating over those of insulin and other vasodilators (68–69). The procoagulant and antifibrinolytic state results from abnormalities of the coagulation cascade and the increase in PAI-1 activity (54,71–73). Associated with, and probably part of, the insulin resistance syndrome is an increase in arterial inflammatory processes that are marked by elevated levels of fibrinogen and plasma CRP levels as measured by a highly sensitive assay (74–76). Many studies have documented the association between insulin resistance and endothelial dysfunction (66,69), the dyslipidemia of high plasma triglycerides, low plasma HDL cholesterol, and a pattern of small dense LDL particles (77–79), the procoagulant state, the low-grade inflammatory state, and, in some populations, increased blood pressure and microalbuminuria (80). These same metabolic abnormalities have all been shown to increase CVD morbidity and mortality risk (37,42,48,49,80). Thus insulin resistance is a metabolic abnor- mality that increases cardiovascular disease risk. In the type 2 diabetic, cardiovascular risks are due to two factors, the insulin resistance syndrome and poorly controlled hyperglycemia (Fig. 6). In contrast to type 1 diabetic patients, type 2 diabetic patients require treatment of both abnormalities from the onset of the illness. Types of Diabetes 25 Figure 6 A hypothesis for the pathogenesis of macrovascular disease in type 2 diabetic patients. Visceral obesity leads to the development of insulin resistance and the other components of the insulin resistance syndrome. The insulin resistance syndrome itself causes accelerated atherosclerosis, which increases clinical macrovascular disease events. In those individuals with the genetic predisposition for type 2 diabetes, the insulin resistance, which increases the requirement for insulin secretion, accelerates beta-cell func- tional failure and this eventually results in first postprandial and later fasting hyperglycemia. The hyperglycemia further contributes to atherogenesis and macrovascular disease by the mechanisms shown in the figure. (Adapted from Ref. 8.) III. CONCLUSIONS AND THERAPEUTIC IMPLICATIONS From the point of view of understanding and preventing or treating the macrovascular complications of diabetes mellitus, it is important to differentiate whether the diabetes is or is not associated with insulin resistance. If it is not initially associated with insulin resistance, as in type 1 or insulin-sensitive type 2 diabetes, then the primary goal should be to treat to and maintain the fasting and postprandial plasma glucose as close to normal as possible, while minimizing the development of visceral obesity. Such a strategy, if it can be implemented, should maintain atherosclerosis progression at the prediabetic level. If, however, insulin resistance is the early event, it should be treated as aggressively as possible in order to prevent accelerated atherosclerosis and the 26 Lebovitz possible progression to type 2 diabetes. The rate of development of atherosclerosis varies in different populations depending on their genetic background and lifestyle (3,81). The acquisition of insulin resistance or diabetes mellitus increases the intrinsic rate of atherosclerosis (82). Populations such as the Pima Indians, who have a low rate of CHD, increase the prevalence two- to threefold with the development of IGT or type 2 diabetes. The absolute prevalence, however, is still significantly lower than that in most nondiabetic populations who have relatively high intrinsic rates of CHD (83). Insulin resistance usually starts and has been accelerating atherosclerosis years before glucose intolerance and type 2 diabetes become evident. By the time IGT or type 2 diabetes is diagnosed, individuals already have advanced atherosclerosis and are on their way to developing clinical macrovascular disease. This likely explains the observations that a diabetic without any preceding clinical CVD has the same likelihood of having a myocardial infarction in a 7-year follow-up as a nondiabetic individuals who already has had a myocardial infarction (84). The suggestion has been made that all type 2 diabetic patients should be treated to prevent progression of their atherosclerosis and that this would be comparable to secondary intervention rather than primary prevention. There are data to suggest that such a strategy, while probably good, may not be good enough. The results of the 6.4-year mean follow-up of the Cardiovascular Health Study indicated ‘‘that most of the traditional cardiovascular risk factors were not significant predictors of the risk of CVD among diabetics after adjusting for the extent of subclinical disease’’ (Table 6) (85). Subclinical disease was defined as an ankle-arm index Յ0.9; internal carotid artery wall thickness Ͼ80th percentile; carotid stenosis Ͼ25%; major ECG abnormalities (based on Minne- Table 6 Multivariate Analysis of Clinical Endpoints as a Function of Subclinical Disease and CVD Risk Factors in Diabetic Participants Without a History of Baseline Clinical Disease Outcome a Variables CVD mortality Incident CHD Subclinical disease 2.51 1.99 Serum creatinine (per 1 mg/dL) 2.15 Fasting plasma glucose (per 20 mg/dL) 1.06 Diastolic BP (per 10 mmHg) 1.18 1.18 Plasma triglycerides (per 20 mg/dL) 1.07 Source: Ref. 85. a Adjusted relative risk. Types of Diabetes 27 sota code); and a Rose Questionnaire positive for claudication or angina pectoris in the absence of clinical diagnosis of angina pectoris or claudication. Subclinical disease was present in 60% of participants with IGT. One can interpret these types of data to provide the following chronology. The insulin resistance syndrome starts at a relatively young age (young adulthood) and causes accelerated atherosclerosis. By middle age, subclinical macrovascular disease is present. In those individuals with the genetic propensity, beta-cell insulin secretory function decreases and impaired glucose tolerance and finally type 2 diabetes develop. By the time type 2 diabetes does develop, subclinical and, in some cases, clinical macrovascular disease is well established and will continue to progress. Poorly controlled hyperglycemia even further accelerates the rate of atherosclerosis. The implications of this hypothesis have far-reaching clinical implications. It means that accelerated atherosclerosis starts at a relatively young age, long before there is any clinical disease and before we would traditionally intervene. This is the stage at which treatment of insulin resistance and cardiovascular risk factors are likely to be most effective in reducing macrovascular disease. 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U.K. Prospective Diabetes Study Group. Ethnicity and cardiovascular disease. The incidence of myocardial infarction in white South Asian, and Afro-Caribbean patients with type 2 diabetes (U.K. Prospective Diabetes Study 32). Diabetes Care 1998; 21:1271–1277. 48. Pyo ¨ ra ¨ la ¨ M, Miettinen H, Halonen P, Laakso M, Pyo ¨ ra ¨ la ¨ K. Insulin resistance syndrome predicts the risk of coronary heart disease and stroke in healthy middle-aged men. The 22-year follow-up results of the Helsinki policemen study. Arterioscler Thromb Vasc Biol 2000; 20:538–544. [...]... Gagnon DR Diabetes, fibrinogen, and the risk of cardiovascular disease: The Framingham experience Am Heart J 1999; 120 :6 72 676 Kohler HP, Grant PJ Plasminogen-activator inhibitor type 1 and coronary artery disease N Engl J Med 20 00; 3 42: 17 92 1801 Danesh J Smoldering arteries? Low-grade inflammation and coronary heart disease JAMA 1999; 28 2 :21 69 21 70 Danesh J, Collins R, Appleby P, Peto R Association of fibrinogen,... kinase plays an essential role for many, if not all, of the biological effects of insulin (21 24 ) Further, insulin receptor tyrosine kinase plays a major role in signal transduction distal to the receptor, as activation results in tyrosine phosphorylation of insulin receptor substrates (IRSs), including IRS-1, IRS -2 , IRS3, IRS-4, Grb -2 , and SHC (21 ,22 ,25 29 ) The IRS proteins are cytoplasmic proteins with... phosphorylation and inactivation of GSK-3 by insulin (63) Specific inhibition of PI-3 kinase by wortmannin in rat L6 cells, which also decreases Glut-4 translocation and activation, prevented the inactivation of insulin on GSK-3 and the activation of p90RSK, p70S6K, and the MAP-kinases (64) The activation of protein kinase B (PKB) is Recognition and Assessment of Insulin Resistance 43 prevented by blocking PI-3... O’Leary DH, Savage PJ Diabetes mellitus: Subclinical cardiovascular disease and risk of incident cardiovascular disease and all-cause mortality Arterioscler Thromb Vasc Biol 20 00; 20 : 823 – 829 3 Recognition and Assessment of Insulin Resistance William T Cefalu University of Vermont College of Medicine, Burlington, Vermont I INTRODUCTION Insulin resistance, defined as an attenuation of normal insulin action,... factor in the development of type 2 diabetes and the early development of accelerated atherosclerosis As such, the natural history of type 2 diabetes suggests that patients may be euglycemic and have normal insulin levels for many years before the development of the disease In the presence of obesity and a family history of diabetes, insulin resistance typically is present and the individual will need... fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease Meta-analyses of prospective studies JAMA 1998; 27 9:1477–14 82 Brunzell JD, Hokanson JE Dyslipidemia of central obesity and insulin resistance Diabetes Care 1999; 22 (suppl 3):C10–C13 Nadler ST, Stoehr JP, Schueler KL, Tanimoto G, Yandell BS, Attie AD The expression of adipogenic genes is decreased in obesity and diabetes. .. kinase (PI-3 kinase) Insulin stimulation increases the amount of PI-3 kinase associated with IRS, and PI-3 kinase activity is directly activated by docking with the IRS proteins (21 ,22 ,26 ,27 ,31) Specifically, binding of IRSs to the regulatory subunit of phosphatidylinositol-3-OH kinase at SHC homology 2 domains results in activation of PI-3 kinase, which appears necessary for insulin action on glucose... mediated by translocation of a large number of glucose transporters from an intracellular pool to the plasma membrane ( 42) The glucose transporters consist of at least five homologous transmembrane proteins (Glut-1, -2 , -3 , -4 , and -5 ) encoded by distinct genes, and have distinct specificities, kinetic properties, and tissue distribution that define their clinical role ( 42) Glut1 and Glut-4 are two major glucose... and pseudoacromegaly: A disorder characterized by selective postreceptor insulin resistance J Clin Invest 1998; 101:1111–1 120 32 66 Lebovitz Calles-Escandon J, Cipolla M Diabetes and endothelial dysfunction: A clinical perspective Endocrine Rev 20 01; 22 :36– 52 67 Zeng G, Nystrom FH, Ravichandran LV, Cong L-N, Kirby M, Mostowski H, Quon MJ Roles for insulin receptor, PI 3-kinase, and Akt in insulin-signaling... some or none of the features of the insulin resistance syndrome or syndrome X (From Ref 6.) II INSULIN RESISTANCE IN THE NATURAL HISTORY OF TYPE 2 DIABETES Reduced insulin-dependent glucose transport is frequently found in nondiabetic relatives and offspring of patients with type 2 diabetes (5) This observation, as demonstrated in families and populations with a high incidence of type 2 diabetes, suggests . Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 20 01; 24 (suppl 1):S5–S20. 2. Wingard DL, Barrett-Cannor E. Heart disease and diabetes. In: Diabetes. in tyrosine phosphorylation of insulin receptor substrates (IRSs), including IRS-1, IRS -2 , IRS- 3, IRS-4, Grb -2 , and SHC (21 ,22 ,25 29 ). The IRS proteins are cytoplasmic proteins with multiple. Framingham Offspring Study. JAMA 20 00; 28 3 :22 1 22 8. 74. Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. Elevated C-reactive protein levels in overweight and obese adults. JAMA 1999; 28 2 :21 31 21 35. 75.

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