PIOGLITAZONE ATTENUATE CORONARY HEART DISEASE RISK FACTORS IN SMOKERS

这个子项目是众多研究子项目之一

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In 1992 we demonstrated that smokers were insulin resistant and hyperinsulinemic when compared to a matched group of non-smokers. In addition to these studies showing smoking to be associated with direct measures of insulin resistance, other population-based reports have indicated that smokers have higher insulin levels (a surrogate marker of insulin resistance) than do non-smokers. Furthermore, despite the observation that smoking cessation was associated with weight gain, it was possible to document an improvement in insulin sensitivity at the same time. Finally, smoking has been shown to accentuate degree of insulin resistance in patients with type 2 diabetes. Consequently, there is considerable support for the view that smokers are insulin resistant and hyperinsulinemic as compared to non-smokers. The fact that smokers have higher plasma triglyceride (TG) and lower high-density lipoprotein cholesterol (HDL-C) concentrations than non-smokers has been apparent for many years. We were able to demonstrate that insulin resistance, compensatory hyperinsulinemia, and a high TG and low HDL-C concentration appeared together as a cluster in smokers. The association between smoking, insulin resistance and dyslipidemia has been also observed in subsequent studies showing the powerful impact of the combined effects of smoking and hyperinsulinemia on plasma TG and HDL-C concentrations in patients with combined hyperlipidemia, and that the cluster of metabolic abnormalities associated with insulin resistance and compensatory hyperinsulinemia were increased six-fold in smokers. The clinical relevance of this association has been emphasized by evidence showing that the increased prevalence of CVD in smokers was almost entirely confined to those individuals that also had high TG and low HDL-Cconcentrations. Several lines of evidence have shown that endothelial function is abnormal when smokers are compared to non-smokers. For example, endothelial-dependent blood flow following venous occlusion is decreased in smokers. The possibility that insulin resistance and/or compensatory hyperinsulinemia mediate the association between smoking and endothelial dysfunction is consistent with several lines of evidence. There are significant relationships between insulin resistance and/or compensatory hyperinsulinemia and markers of endothelial dysfunction. Although these changes in lipoprotein metabolism and endothelial function provide attractive mechanistic links between smoking and CHD, it does not necessarily mean that either abnormality is an independent risk factor. More specifically, there is evidence that insulin resistance and compensatory hyperinsulinemia lead to both dyslipidemia and endothelial dysfunction. Thus, it is possible that a major defect leading to increased CHD risk in smokers is insulin resistance, and that the multiple consequences associated with this abnormality, including compensatory hyperinsulinemia, dyslipidemia, and endothelial dysfunction, are responsible for the accelerated atherogenesis. If this hypothesis is correct, attenuation of insulin resistance in smokers should result in a decrease in CHD risk factors associated with this basic abnormality in insulin metabolism. We propose to test this hypothesis by identifying cigarettes smokers who are insulin resistant, and to treat them with pioglitazone. We predict that this intervention will enhance insulin sensitivity in these individuals, and significantly decrease multiple CHD risk factors.