PIOGLITAZONE ATTENUATE CORONARY HEART DISEASE RISK FACTORS IN SMOKERS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 1992年，我们证明了吸烟者与匹配的非吸烟者组相比，存在胰岛素抵抗和高胰岛素血症。除了这些研究表明吸烟与胰岛素抵抗的直接测量有关外，其他基于人群的报告还表明，吸烟者的胰岛素水平(胰岛素抵抗的替代标志)比不吸烟者高。此外，尽管观察到戒烟与体重增加有关，但同时也有可能证明胰岛素敏感性的改善。最后，吸烟已被证明会加剧2型糖尿病患者的胰岛素抵抗程度。因此，与非吸烟者相比，吸烟者具有胰岛素抵抗和高胰岛素血症的观点得到了相当大的支持。 吸烟者比不吸烟者有更高的甘油三酯(TG)和更低的高密度脂蛋白胆固醇(HDL-C)浓度，这一事实多年来一直很明显。我们能够证明，在吸烟者中，胰岛素抵抗、代偿性高胰岛素血症、高甘油三酯和低高密度脂蛋白浓度一起出现。在随后的研究中也观察到了吸烟、胰岛素抵抗和血脂异常之间的联系，这些研究表明吸烟和高胰岛素血症的综合效应对混合型高脂血症患者的血浆甘油三酯和高密度脂蛋白胆固醇浓度有很大的影响，而且与胰岛素抵抗和代偿性高胰岛素血症相关的代谢异常簇在吸烟者中增加了6倍。有证据表明，吸烟者心血管疾病患病率的增加几乎完全局限于那些同时具有高甘油三酯和低高密度脂蛋白胆固醇浓度的个体，这一关联的临床相关性得到了强调。 一些证据表明，当吸烟者与不吸烟者进行比较时，内皮功能是异常的。例如，在吸烟者中，静脉闭塞后的内皮依赖性血流减少。 胰岛素抵抗和/或代偿性高胰岛素血症调节吸烟和内皮功能障碍之间的联系的可能性与几条证据相一致。胰岛素抵抗和/或代偿性高胰岛素血症与内皮功能障碍的标志物有显著关系。 尽管这些脂蛋白代谢和内皮功能的变化在吸烟和CHD之间提供了诱人的机制联系，但这并不一定意味着任何一种异常都是一个独立的危险因素。更具体地说，有证据表明胰岛素抵抗和代偿性高胰岛素血症会导致血脂异常和内皮功能障碍。因此，导致吸烟者CHD风险增加的一个主要缺陷可能是胰岛素抵抗，与这种异常相关的多种后果，包括代偿性高胰岛素血症、血脂异常和内皮功能障碍，是加速动脉粥样硬化的原因。如果这一假设是正确的，吸烟者胰岛素抵抗的减弱应该会导致与胰岛素代谢基本异常相关的冠心病危险因素的减少。我们建议通过识别胰岛素抵抗的吸烟者来检验这一假设，并用吡格列酮治疗他们。我们预测，这种干预将增强这些个体的胰岛素敏感性，并显著降低多种CHD危险因素。

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.