Inflammation and Insulin Resistance in Rheumatoid Arthritis

类风湿关节炎的炎症和胰岛素抵抗

基本信息

批准号：
8381910
负责人：
C M STEIN
金额：
$ 31.18万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8381910
关键词：
2,4-thiazolidinedione Adrenal Cortex Hormones Affect Age Agonist Animal Model Animals Arthritis Atherosclerosis Attention Blood Glucose Body mass index C-reactive protein Cardiovascular Diseases Cardiovascular system Central obesity Chronic Clinical Research Coronary Arteriosclerosis Coronary artery Data Development Diabetes Mellitus Disease Dyslipidemias Employee Strikes Evaluation General Population Human Hyperinsulinism Hypertension IL6 gene Individual Inflammation Inflammation Mediators Inflammation Process Inflammatory Insulin Insulin Resistance Interleukin-6 Joints Ligands Measures Metabolic syndrome Modeling Morbidity - disease rate Myocardial Ischemia Nuclear Outcome Patients Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Pioglitazone Placebos Population Prevalence Race Randomized Rheumatoid Arthritis Severities TNF gene Testing Thiazolidinediones cardiovascular risk factor improved in vivo indexing inflammatory marker insulin sensitivity insulin sensitizing drugs man mortality multidisciplinary novel strategies premature atherosclerosis prevent sex tool transcription factor translational study

项目摘要

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.

RA 中的炎症和胰岛素抵抗类风湿性关节炎 (RA) 影响着大约 1% 的人口，并且与缺血性心脏病患病率增加有关。我们已经表明，RA 患者冠状动脉粥样硬化的患病率显着增加，但其潜在机制尚不清楚。在初步研究中，我们发现 RA 患者的胰岛素浓度比对照组高 2 倍以上，并且与 IL6、TNF 和 CRP 等炎症标志物以及冠状动脉粥样硬化相关。因此，炎症和高胰岛素血症等相关过程在机制上导致 RA 心血管发病率增加。高胰岛素血症和炎症之间的关系是双向的——炎症促进胰岛素抵抗，而胰岛素抵抗则促进慢性炎症。噻唑烷二酮类，选择性 PPARy 激动剂，即使在没有糖尿病的个体中也是胰岛素增敏剂，并且是了解炎症和胰岛素抵抗之间关系的机制的有力工具。噻唑烷二酮类药物不仅可以提高胰岛素敏感性，还可以减少动物模型中的炎症，包括关节炎。因此，在一项概念验证转化研究中，我们将随机分配 RA 患者接受吡格列酮或安慰剂治疗 6 个月，以测试 PPARγ 激动剂治疗将减少炎症（具体目标 1）、改善胰岛素敏感性（具体目标 1）的假设。目标 2) 并改善 RA 患者的增强指数（具体目标 3）。拟议的研究将提供有关炎症和高胰岛素血症之间关系的机制信息，并将确定新的策略可能逆转或预防 RA 以及其他炎症性疾病对关节和脉管系统的长期损害。