Hemostatic abnormalities associated with obesity and the metabolic syndrome

Insulin-mediated glucose disposal varies 6–8-fold in apparently healthy human beings [1], a degree of variability that far exceeds that seen with any other basic physiological function. Although there is evidence that the variation in insulin action is under genetic regulation, as much as 50% of the variability in insulin-mediated glucose disposal within a population of normal volunteers is secondary to difference in life style. In this context, obesity and decreased physical activity play particularly crucial roles, each contributing approximately equally to the variability in insulin-mediated glucose disposal seen in the population at large [2]. It is also worth noting that powerful ethnic differences exist, with essentially every other ethnic group studied being more insulin resistant than individuals of European ancestry. When insulin-resistant individuals cannot secrete enough insulin to overcome this defect, glucose intolerance supervenes. However, the ability of hyperinsulinemia to prevent decompensation of glucose tolerance appears to be a mixed blessing. Individuals that are insulin resistant and hyperinsulinemic are more likely to develop essential hypertension, and have a dyslipidemia characterized by a high plasma triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentration. All of these changes have also been shown to increase risk of cardiovascular disease (CVD), and in 1988 [3] these relationships were explicitly addressed and designated as comprising a Syndrome (X). Since the introduction of the concept of Syndrome X, many other abnormalities have been shown to be associated with insulin resistance/compensatory hyperinsulinemia and CVD [4]. For example, the dyslipidemia associated with insulin resistance/compensatory hyperinsulinemia also includes the appearance of smaller, low-density lipoprotein (LDL) particles and the enhanced postprandial accumulation of remnant lipoproteins; both of these latter changes have also been identified as increasing risk of CVD. Evidence is also rapidly accumulating that emphasizes the link between insulin resistance/compensatory hyperinsulinemia, various aspects of endothelial dysfunction, and CVD risk. For example, binding of isolatedmononuclear cells to the endothelium is the first step in the process of atherogenesis, and the more insulin resistant an individual, the greater will be the adherence of their mononuclear cells to cultured endothelium. Adhesion molecules produced by endothelial cells modulate the binding of mononuclear cells to endothelium, and there is a statistically significant relationship between degree of insulin resistance and the plasma concentration of several of these adhesion molecules. Further evidence of the relationship between insulin resistance and endothelial dysfunction is the finding that asymmetric dimethylarginine (ADMA), an endogenous inhibitor of the enzyme nitric oxide synthase, is increased in insulinresistant/hyperinsulinemic individuals. More recently, the potential important role that several inflammatory markers may play in both insulin resistance and CVD risk has been under active investigation. Last, but certainly not least, is the importance of increases in circulating procoagulant factors that occur in insulin-resistant individuals, and make their own contribution to the increased CVD that characterizes the insulin resistance syndrome. It is obvious that the cluster of abnormalities associated with insulin resistance and compensatory hyperinsulinemia contains many well-recognized CVD risk factors, and choosing which one, or ones, that are primarily responsible for the accelerated atherogenesis that characterizes this syndrome is not a simple task. Indeed, efforts to do so by the use of multiple regression analysis of epidemiological data may be more misleading than helpful, given the manner in which these abnormalities cluster togetherwithin a given individual. For example, we have shown [5] that insulin-resistant women, when matched with insulinsensitive women for age, body mass index, and waist circumference, in addition to having significantly higher plasminogen activator inhibitor (PAI)-1 concentrations, had significantly higher plasma insulin and TG concentrations, and lower levels of HDL-C. Furthermore, PAI-1 levels in the group as a whole were significantly correlated with degree of insulin resistance, and fasting plasma insulin, TG, and HDL-C concentrations. Correspondence: Professor G. Reaven, Division of Cardiovascular Medicine, Falk CVRC, Stanford Medical Center, 300 Pasteur Drive, Stanford, CA 94305-5406, USA. 2 Tel.: +1 650 724 3416; fax: +1 640 725 1599; e-mail: greaven@cvmed. stanford.edu Journal of Thrombosis and Haemostasis, 3: 1074–1085