Inflammation and Insulin Resistance in Rheumatoid Arthritis

类风湿关节炎的炎症和胰岛素抵抗

• 批准号: 7912914
• 负责人: C M STEIN
• 金额: $ 30.82万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7912914
• 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

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.

炎症与类风湿关节炎胰岛素抵抗 风湿性关节炎（RA）影响大约1%的人群，并且与关节炎相关。 缺血性心脏病的患病率增加。我们已经证明， RA患者动脉粥样硬化明显增加，但其潜在机制 不知道。在初步研究中，我们发现胰岛素浓度是 在RA患者中高于对照组，并且与炎症标志物如IL 6相关， TNF和CRP与冠状动脉粥样硬化的关系。因此，相关的过程，炎症和 高胰岛素血症在机制上导致RA心血管发病率增加。的 高胰岛素血症和炎症之间的关系是双向的-炎症促进 胰岛素抵抗和胰岛素抵抗促进慢性炎症。噻唑烷二酮类， 选择性PPARy激动剂是胰岛素增敏剂，即使在没有糖尿病的个体中也是胰岛素增敏剂，并且是一种抗胰岛素受体。 了解炎症和炎症之间关系的机制的有力工具。 胰岛素抵抗噻唑烷二酮类药物不仅能改善胰岛素敏感性， 炎症，包括动物模型中的关节炎。因此，在概念验证翻译研究中， 我们将RA患者随机接受吡格列酮或安慰剂治疗6个月， 假设用PPAR γ激动剂治疗将减少炎症（特异性目的1）， 改善胰岛素敏感性（具体目标2）和改善增强指数（具体目标3）， RA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，并将确定新的策略， 可能逆转或预防RA关节和血管系统的长期损伤，以及 可能是其他炎症性疾病。