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: 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
• 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

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.

类风湿关节炎的炎症与胰岛素抵抗 类风湿性关节炎(RA)影响着大约1%的人口，并与缺血性心脏病的发病率增加有关。我们的研究表明，RA患者冠状动脉粥样硬化的患病率显著增加，但其潜在机制尚不清楚。在初步研究中，我们发现类风湿关节炎患者的胰岛素浓度是对照组的2倍以上，并且与炎症标记物如IL6、肿瘤坏死因子和C反应蛋白相关，也与冠状动脉粥样硬化有关。因此，相关的过程，炎症和高胰岛素血症，机械地导致类风湿关节炎心血管发病率的增加。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，是了解炎症和胰岛素抵抗之间关系的强大工具。在动物模型中，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，包括关节炎。因此，在一项概念验证翻译研究中，我们将随机让RA患者接受为期6个月的吡格列酮或安慰剂治疗，以测试PPARy激动剂治疗将减少RA患者的炎症(特定目标1)、改善胰岛素敏感性(特定目标2)和提高增强指数(特定目标3)的假设。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，或许还有其他炎症性疾病。