CARDIOVASCULAR DISEASE RISK IN INSULIN RESISTANT DYSLIPIDEMIC INDIVIDUALS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 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 研究中心，而研究中心不一定是研究者所在的机构。 胰岛素抵抗（IR）与心血管疾病（CVD）风险增加有关。 大约1/4的美国人口是IR并且具有IR综合征（IRS）。 IRS与高血浆甘油三酯（TG）和低高密度脂蛋白胆固醇（HDL-C）相关。 这种致动脉粥样硬化的脂蛋白模式还包括餐后脂血症，并与CVD风险增加有关。 目前尚不清楚IR相关的CVD风险是否仅仅是相关脂质和脂蛋白异常的功能，但越来越多的证据表明情况并非如此。 在IR个体中预防CVD的生活方式干预之外的治疗选择包括通过激活核激素受体PPAR-alpha靶向脂质/脂蛋白紊乱的纤维酸化合物，以及最近通过激活相关核激素受体PPAR-gamma直接逆转IR的噻唑烷二酮类药物。 有趣的是，后一类药物似乎对TG和HDL-C浓度没有重大影响，尽管它们降低了胰岛素，葡萄糖和游离脂肪酸，所有这些都有助于肝脏VLDL的产生。 然而，先前的研究受到限制，因为它们仅测量了空腹脂质/脂蛋白，并且它们没有专门针对高TG和/或低HDL-C的个体。 此外，虽然已经研究了噻唑烷二酮类药物对早期CVD标志物（如促炎细胞因子、C-反应蛋白和粘附分子）的影响，但关于贝特类药物对这些变量的影响的数据很少。 计划的研究将比较这两类药物对高TG和低HDL-C的IR个体的CVD风险的影响。 主要终点将包括空腹和餐后血脂和致动脉粥样硬化残余脂蛋白，沿着CVD的替代标志物，如C-反应蛋白、不对称二甲基精氨酸和粘附分子。 协变量将包括IR、葡萄糖、胰岛素和游离脂肪酸浓度的变化。 我们假设，虽然贝特类药物对空腹和餐后脂质/脂蛋白谱的影响相对较大，噻唑烷二酮对胰岛素和葡萄糖代谢的影响相对较大，但两种药物均会降低早期CVD（炎症和内皮功能障碍）的循环标志物。

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. Insulin resistance (IR) is known to be associated with an increased risk for cardiovascular disease (CVD). Approximately 1/4 of the US population is IR and has the IR syndrome (IRS). IRS is associated with a high plasma triglyceride (TG) and a low high-density lipoprotein cholesterol (HDL-C). This atherogenic lipoprotein pattern also includes postprandial lipemia and is associated with an increased risk for CVD. It is unclear whether the CVD risk associated with IR is merely a function of the associated lipid and lipoprotein abnormalities, but increasing evidence suggests that this is not the case. Treatment options beyond lifestyle interventions to prevent CVD in IR individuals include fibric acid compounds that target the lipid/lipoprotein disturbances via activation of the nuclear hormone receptor PPAR-alpha, and more recently, the thiazolidenedione class of drugs that directly reverse the IR via activation of the related nuclear hormone receptor, PPAR-gamma. Interestingly, the latter class of drugs does not appear to have a major effect on TG and HDL-C concentrations despite the fact that they lower insulin, glucose, and free fatty acids, all of which contribute to hepatic VLDL production. However, prior studies have been limited in that they have measured only fasting lipid/lipoproteins, and they have not specifically targeted individuals with high TG and/or low HDL-C. Furthermore, while the thiazolidenediones have been studied with respect to markers of early CVD such as pro-inflammatory cytokines, C-reactive protein and adhesion molecules, there is little data on the effect of fibrates on these variables. The planned study will compare the effect of these two classes of drugs on CVD risk in IR individuals who have high TG and low HDL-C. Primary endpoints will include fasting and postprandial lipids and atherogenic remnant lipoproteins, along with surrogate markers of CVD such as C-reactive protein, asymmetric dimethylarginine, and adhesion molecules. Covariates will include change in IR, glucose, insulin, and free fatty acid concentrations. We hypothesize that while the fibrate will have a relatively greater effect on the fasting and postprandial lipid/lipoprotein profile, and the thiazolidenedione will have a relatively greater effect on insulin and glucose metabolism, circulating markers of early CVD (inflammation and endothelial dysfunction) will be reduced with both drugs.