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. Hypothesis: This study is aimed at evaluating the following two hypothesis: 1. Smokers are more insulin-resistant than non-smokers, and that the consequences of this defect in insulin action-hyperinsulinemia, high plasma triglyceride (TG) and low high density lipoprotein cholesterol (HDL-C), and endothelial dysfunction-provide a mechanistic link between smoking and cardiovascular disease (CVD). 2. Administration of Pioglitazone (PIO) to insulin-resistant cigarette smokers will enhance insulin-mediated glucose disposal in these individuals, thereby decreasing their degree of compensatory hyperinsulinemia, and improving both their lipid abnormalities and endothelial function. Goals: We have previously demonstrated that, when compared to a matched group of non-smokers, smokers are insulin-resistant and hyperinsulinemic. That initial report was soon confirmed, and additional studies have shown that smokers have higher insulin levels (a surrogate marker of insulin resistance) when compared to non-smokers. It has also been apparent for some time that smokers have higher plasma TG and lower HDL-C concentrations than non-smokers. Indeed, it was the similarity between the dyslipidemia described in smokers and that found in insulin-resistant individuals generally that led to the initiation of our study of insulin resistance in smokers. In that study, 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. Subsequent studies have contributed substantial evidence that the combination of insulin resistance, hyperinsulinemia, and the dyslipidemia characteristic of insulin resistance occur together in smokers more commonly than in non-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-C concentrations. Additionally, several lines of evidence have shown that endothelial function is abnormal in smokers when compared to non-smokers, and that plasma concentrations of cellular adhesions molecules (CAMs) are increased in smokers in association with higher plasma insulin concentrat
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