Inflammation and Insulin Resistance in Rheumatoid Arthritis

类风湿关节炎的炎症与胰岛素抵抗 类风湿性关节炎(RA)，影响大约1%的人口，并与 缺血性心脏病患病率增加。我们已经证明，冠心病的患病率 动脉粥样硬化在RA患者中显著增加，但其潜在机制 都是未知的。在初步研究中，我们发现胰岛素浓度是原来的两倍多。 类风湿关节炎患者较对照组升高，并与炎症标志物如IL-6相关， 肿瘤坏死因子、C反应蛋白与冠状动脉粥样硬化的关系。因此，相关的过程、炎症和 高胰岛素血症是类风湿关节炎心血管发病率增加的机械性因素。这个 高胰岛素血症与炎症的关系是双向的--炎症促进 胰岛素抵抗，而胰岛素抵抗会促进慢性炎症。噻唑烷二酮类， 选择性PPARy激动剂，即使在没有糖尿病的人中也是胰岛素增敏剂，是一种 一种强大的工具，可用于了解炎症和炎症之间关系的潜在机制 胰岛素抵抗。噻唑烷二酮类药物，不仅能改善胰岛素敏感性，还能降低 炎症，包括动物模型中的关节炎。因此，在一项概念验证翻译研究中， 我们将随机选择类风湿关节炎患者接受吡格列酮或安慰剂治疗6个月，以测试 假设使用PPARy激动剂治疗将减少炎症(特定目标1)， 改善胰岛素敏感性(特指2)和改善增强指数(特指3) 类风湿关节炎患者。拟议的研究将提供有关 炎症和高胰岛素血症之间的关系，并将确定新的治疗策略 有可能逆转或预防对RA关节和血管系统的长期损害，以及 也许是其他炎症性疾病。

Inflammation and Insulin Resistance in RA Rheumatoid arthritis (RA), affects approximately 1% of the population and is associated with an increased prevalence of ischemic heart disease. We have shown that the prevalence of coronary artery atherosclerosis is increased markedly in patients with RA, but the underlying mechanisms are not known. In preliminary studies we found that insulin concentrations are more than 2-fold higher in patients with RA than controls and are correlated with inflammatory markers such as IL6, TNF and CRP, and with coronary atherosclerosis. Thus, related processes, inflammation and hyperinsulinemia, contribute mechanistically to increased cardiovascular morbidity in RA. The relationship between hyperinsulinemia and inflammation is bi-directional - inflammation facilitates insulin resistance, and insulin resistance promotes chronic inflammation. Thiazolidinediones, selective PPARy agonists, are insulin sensitizers even in individuals without diabetes and are a powerful tool to understand the mechanisms underlying the realtionship between inflammation and insulin resistance. Thiazolidinediones, not only improve insulin sensitivity, but also decrease inflammation, including arthritis in animal models. Thus, in a proof-of-concept translational study, we will randomize patients with RA to receive pioglitazone or placebo for 6 months to test the hypotheses that treatment with a PPARy agonist will decrease inflammation (Specific Aim 1), improve insulin sensitivity (Specific Aim 2) and improve augmentation index (Specific Aim 3) in patients with RA. The proposed studies will provide mechanistic information regarding the relationship between inflammation and hyperinsulinemia, and will identify novel strategies for potentially reversing or preventing the long term damage to joints and the vasculature in RA, and perhaps other inflammatory diseases.