The prevalence of insulin resistance in the most common metabolic disorders is still an undefined issue. We assessed the prevalence rates of insulin resistance in subjects with impaired glucose tolerance (IGT), NIDDM, dyslipidemia, hyperuricemia, and hypertension as identified within the frame of the Bruneck Study. The study comprised an age- and sex-stratified random sample of the general population (n = 888; aged 40-79 years). Insulin resistance was estimated by homeostasis model assessment (HOMA(IR)), preliminarily validated against a euglycemic-hyperinsulinemic clamp in 85 subjects. The lower limit of the top quintile of HOMA(IR) distribution (i.e., 2.77) in nonobese subjects with no metabolic disorders (n = 225) was chosen as the threshold for insulin resistance. The prevalence of insulin resistance was 65.9% in IGT subjects, 83.9% in NIDDM subjects, 53.5% in hypercholesterolemia subjects, 84.2% in hypertriglyceridemia subjects, 88.1% in subjects with low HDL cholesterol, 62.8% in hyperuricemia subjects, and 58.0% in hypertension subjects. The prevalence of insulin resistance in subjects with the combination of glucose intolerance (IGT or NIDDM), dyslipidemia (hypercholesterolemia and/or hypertriglyceridemia and/or low HDL cholesterol), hyperuricemia, and hypertension (n = 21) was 95.2%. In isolated hypercholesterolemia, hypertension, or hyperuricemia, prevalence rates of insulin resistance were not higher than that in nonobese normal subjects. An appreciable number of subjects (n = 85, 9.6% of the whole population) was insulin resistant but free of IGT, NIDDM, dyslipidemia, hyperuricemia, and hypertension. These results from a population-based study documented that 1) in hypertriglyceridemia and a low HDL cholesterol state, insulin resistance is as common as in NIDDM, whereas it is less frequent in hypercholesterolemia, hyperuricemia, and hypertension; 2) the vast majority of subjects with multiple metabolic disorders are insulin resistant; 3) in isolated hypercholesterolemia, hyperuricemia, or hypertension, insulin resistance is not more frequent than can be expected by chance alone; and 4) in the general population, insulin resistance can be found even in the absence of any major metabolic disorders.

The current study yields first epidemiologic evidence that endotoxemia constitutes a strong risk factor of early atherogenesis in subjects with chronic or recurrent bacterial infections and a link in the association between cigarette smoking and atherosclerotic disease.

Background-Work from our laboratory has proven that increased titers of anti-heat shock protein 60 (HSP60) antibodies are associated with atherosclerosis and that HSP60-reactive T-cells are present in atherosclerotic lesions. Recent studies from others demonstrated that HSP60 directly activates endothelial cells and macrophages. Methods and Results-To explore the possibility that HSP60 exists in the circulation, where it could exert its functions, we performed a population-based study with 826 subjects aged 40 to 79 years. The following items were measured in all participants: serum soluble HSP60 (sHSP60); anti-Escherichia coli lipopolysaccharide; anti-HSP65, anti-Chlamydia, and anti-Helicobacter pylori antibodies; and a variety of acute phase reactants (C-reactive protein, ␣ 1 -antitrypsin, and ceruloplasmin) and markers of systemic inflammation. Carotid atherosclerosis was assessed twice (1990 and 1995), and 15 other risk factors were evaluated. Our data show that levels of sHSP60 were significantly elevated in subjects with prevalent/incident carotid atherosclerosis and that these levels were correlated with common carotid artery intima/media thickness. Multiple logistic regression analysis documented these associations as independent of age, sex, and other risk factors. Interestingly, sHSP60 was also correlated with anti-lipopolysaccharide, anti-Chlamydia and anti-HSP60 antibodies, various markers of inflammation, and the presence of chronic infections. The risk of atherosclerosis associated with high sHSP60 levels was amplified when subjects had clinical and/or laboratory evidence of chronic infections. Conclusions-Our data provide the first evidence of a strong correlation between sHSP60 and atherosclerosis, suggesting that sHSP60 may play important roles in activating vascular cells and the immune system during the development of atherosclerosis. (Circulation. 2000;102:14-20.)

OBJECTIVE -The purpose of this study was to evaluate whether insulin resistance is associated to cardiovascular disease (CVD) and to understand whether this association can be explained by traditional and novel CVD risk factors associated with this metabolic disorder. RESEARCH DESIGN AND METHODS-We examined a sample representative of the population of Bruneck, Italy (n ϭ 919; aged 40 -79 years). Insulin-resistant subjects were those with a score in the top quartile of the homeostasis model assessment (HOMA) for insulin resistance (HOMA-IR). Risk factors correlated with insulin resistance included BMI, A1C, HDL cholesterol, triglycerides, blood pressure, high-sensitivity C-reactive protein (hsCRP), fibrinogen, oxidized LDL, vascular cell adhesion molecule-1 (VCAM-1), and adiponectin. Subjects without CVD at baseline were followed up for 15 years for incident CVD, a composite end point including fatal and nonfatal myocardial infarction and stroke, transient ischemic attack, and any revascularization procedure.RESULTS -During follow-up, 118 subjects experienced a first symptomatic CVD event. Levels of HOMA-IR were higher at baseline among subjects who developed CVD (2.8) compared with those remaining free of CVD (2.5) (P Ͻ 0.05). Levels of HOMA-IR also were significantly correlated (P Ͻ 0.05) with most CVD risk factors we evaluated. In Cox proportional hazard models, insulin-resistant subjects had an age-, sex-, and smoking-adjusted 2.1-fold increased risk (95% CI 1.3-3.1) of incident symptomatic CVD relative to non-insulin-resistant subjects. After sequential adjustment for physical activity and classic risk factors (A1C, LDL cholesterol, and hypertension) as well as BMI, HDL cholesterol, triglycerides, and novel risk factors, including fibrinogen, oxidized LDL, hsCRP, VCAM-1, and adiponectin, the association between HOMA-IR and incident CVD remained significant and virtually unchanged (hazard ratio 2.2 [95% CI 1.4 -3.6], P Ͻ 0.001).CONCLUSIONS -HOMA-estimated insulin resistance is associated with subsequent symptomatic CVD in the general population independently of all classic and several nontraditional risk factors. These data suggest that insulin resistance may be an important target to reduce CVD risk. Diabetes Care 30:318 -324, 2007I nsulin resistance is a pathogenic factor for type 2 diabetes (1,2) and is associated with diverse cardiovascular disease (CVD) risk states, including obesity, essential hypertension, hypertriglyceridemia, and low HDL cholesterol (3). A significant proportion of apparently healthy subjects also are insulin resistant (4,5). In aggregate, insulin resistance and related conditions are very common, affecting as many as 30 -40% of subjects living in affluent countries. Insulin resistance is also a common finding in developing countries. Throughout the world hundreds of millions of people and perhaps even Ͼ1 billion people are estimated to have insulin resistance (6).In recent years the question as to whether insulin resistance is involved in the pathogenesis of CVD has persisted. This ...

OBJECTIVE -The present study aimed at prospectively evaluating carotid atherosclerosis and coronary heart disease (CHD) in subjects with the metabolic syndrome.RESEARCH DESIGN AND METHODS -Within a prospective population-based survey examining 888 subjects aged 40 -79 years, 303 subjects were identified as fulfilling World Health Organization (WHO) criteria and 158 as fulfilling the National Cholesterol Education Program (NCEP)-Adult Treatment Panel (ATP)-III criteria for diagnosing the metabolic syndrome. The 5-year change in carotid status, as assessed by echo-duplex scanning, and incident fatal and nonfatal CHD, as assessed by medical history and death certificates, were compared in subjects with the metabolic syndrome and in the rest of the sample (control subjects).RESULTS -Compared with the control subjects, subjects with the metabolic syndrome by WHO criteria had an increased 5-year incidence and progression of carotid atherosclerosis: 51 vs. 35% developed new plaques (P ϭ 0.021) and 34 vs. 19% developed carotid stenosis Ͼ40% (P ϭ 0.002) after adjusting for several confounders. Subjects with the metabolic syndrome by these criteria also had an increased incidence of CHD during follow-up: 8 vs. 3% in control subjects (P ϭ 0.012). Similar results were found when the NCEP-ATPIII criteria were used.CONCLUSIONS -Subjects with the metabolic syndrome are at increased risk for both progressive carotid atherosclerosis and CHD.