Mechanisms of Insulin Resistance in Rheumatoid Arthritis

描述(由申请人提供)：类风湿性关节炎(RA)患者患心血管疾病和胰岛素抵抗的风险增加，胰岛素抵抗是代谢心血管疾病的危险因素。在没有类风湿关节炎的个体中，习惯性的体力活动可以改善胰岛素的作用和心血管疾病的发病率。运动对类风湿性关节炎患者带来类似健康益处的可能性还没有被探索。该提案概述了职业培训和研究计划，该计划将为制定具体的干预措施提供基础，从而可以利用体力活动来调节RA的代谢心血管风险。职业发展计划的重点是建立一个翻译研究项目，应用最先进的技术在人类群体中进行机械学研究。该计划的目标如下：1)发展与新陈代谢有关的培训和技能；2)熟练运用骨骼肌活组织检查技术；3)发展运动生理学和体力活动干预方面的专门知识；4)发展临床试验设计和实施方面的技能，并在负责任的研究中获得培训；5)发展统计分析方面的高级技能；以及6)提高手稿准备和拨款撰写方面的技能。我们假设RA相关的炎症和不活动导致骨骼肌萎缩和腹型肥胖增加，进而导致线粒体功能障碍和最终的胰岛素抵抗。这些假说将通过以下具体目标来检验：1)确定与性别、年龄和BMI匹配的对照组相比，RA患者是否改变了身体组成和脂解增加；2)确定RA是否与肌肉消耗相关的信号通路的激活增加和肌肉纤维成分的一致变化有关；3)确定RA患者的肌内脂质失衡和/或线粒体功能障碍是否有助于胰岛素信号转导受损；4)确定与性别、年龄和体重指数匹配的对照组相比，RA患者是否存在胰岛素抵抗，并评估RA患者胰岛素敏感性的预测因素，包括身体成分、脂肪分解以及与肌肉萎缩和胰岛素脱敏有关的信号通路的激活。因此，这项工作将探索适用于非药物治疗类风湿性关节炎的创新假设，并实施一个全面的研究计划，试图加深我们对人类疾病机制的理解。

DESCRIPTION (provided by applicant): Persons with rheumatoid arthritis (RA) are at increased risk of cardiovascular (CV) disease and insulin resistance, a metabolic CV risk factor. In individuals without RA, habitual physical activity improves insulin action and CV morbidity. The potential for exercise to confer similar health benefits in RA patients has not been explored. This proposal outlines a career training and research plan that will provide the basis for developing specific interventions whereby physical activity can be used to modulate metabolic CV risk in RA. The career development plan focuses on building a translational research program that applies state-of-the-art technology to perform mechanistic studies in human populations. The objectives of this plan are as follows: 1) To develop training and skills relevant to metabolism; 2) To perform and gain proficiency in skeletal muscle biopsy techniques; 3) To develop expertise in exercise physiology and physical activity interventions; 4) To develop skills in clinical trial design and implementation and obtain training in the responsible conduct of research; 5) To develop advanced skills in statistical analysis; and 6) To advance skills in manuscript preparation and grant writing. We hypothesize that RA-associated inflammation and inactivity mediate skeletal muscle atrophy and increased abdominal obesity, which in turn lead to mitochondrial dysfunction and eventual insulin resistance. These hypotheses will be tested via the following specific aims: 1) To determine whether persons with RA have altered body composition and increased lipolysis compared with sex-, age- and BMI-matched controls; 2) To determine whether RA associates with heightened activation of signaling pathways involved in muscle wasting and coincident changes in muscle fiber composition; 3) To determine whether intramuscular lipid imbalance and/or mitochondrial dysfunction in persons with RA contributes to impaired insulin signaling; and, 4) To determine whether persons with RA are insulin resistant, relative to sex-, age- and BMI-matched controls, and to evaluate predictors of insulin sensitivity in RA patients, including body composition, lipolysis, and activation of signaling pathways implicated in muscle wasting and insulin desensitization. Thus, this work will explore innovative hypotheses applicable to a non-pharmacologic treatment approach to RA, and implement a comprehensive research program that seeks to deepen our understanding of the mechanisms of human disease.