CAN PIOGLITAZONE ATTENUATE CORONARY HEART DISEASE RISK FACTORS?

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。假设：本研究旨在评估以下两个假设：1。吸烟者比非吸烟者更易产生胰岛素抵抗，这种胰岛素作用缺陷的后果-高胰岛素血症、高血浆甘油三酯（TG）和低高密度脂蛋白胆固醇（HDL-C）以及内皮功能障碍-提供了吸烟与心血管疾病（CVD）之间的机制联系。2.对胰岛素抵抗的吸烟者给予吡格列酮（PIO）将增强这些个体中胰岛素介导的葡萄糖处置，从而降低其代偿性高胰岛素血症的程度，并改善其脂质异常和内皮功能。 目的：我们先前已经证明，与一组匹配的非吸烟者相比，吸烟者具有胰岛素抵抗和高胰岛素血症。最初的报告很快得到了证实，更多的研究表明，与非吸烟者相比，吸烟者的胰岛素水平更高（胰岛素抵抗的替代标志物）。 一段时间以来，吸烟者的血浆TG浓度高于非吸烟者，HDL-C浓度低于非吸烟者。事实上，正是吸烟者中描述的血脂异常与胰岛素抵抗个体中发现的血脂异常之间的相似性导致了我们对吸烟者胰岛素抵抗的研究。在这项研究中，我们能够证明，胰岛素抵抗，代偿性高胰岛素血症，高TG和低HDL-C浓度一起出现在吸烟者中。随后的研究提供了大量证据，表明胰岛素抵抗、高胰岛素血症和胰岛素抵抗特征性血脂异常的组合在吸烟者中比在非吸烟者中更常见。有证据表明，吸烟者中CVD患病率的增加几乎完全局限于那些也具有高TG和低HDL-C浓度的个体，从而强调了这种关联的临床相关性。此外，一些证据表明，与非吸烟者相比，吸烟者的内皮功能异常，吸烟者的血浆细胞粘附分子（CAM）浓度升高，与较高的血浆胰岛素浓度相关。

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