Mechanisms of Insulin Resistance in Rheumatoid Arthritis

描述（由申请人提供）：类风湿性关节炎（RA）患者发生心血管（CV）疾病和胰岛素抵抗（代谢性CV风险因素）的风险增加。在没有RA的个体中，习惯性体力活动改善胰岛素作用和CV发病率。尚未探索运动对RA患者产生类似健康益处的潜力。该提案概述了一项职业培训和研究计划，该计划将为制定特定干预措施提供基础，从而可以使用体力活动来调节RA的代谢CV风险。职业发展计划的重点是建立一个转化研究计划，应用最先进的技术在人群中进行机械研究。本计划的目标如下：1）开发与代谢相关的培训和技能; 2）执行并熟练掌握骨骼肌活检技术; 3）开发运动生理学和体力活动干预方面的专业知识; 4）开发临床试验设计和实施方面的技能，并获得负责任开展研究方面的培训; 5）培养统计分析方面的高级技能; 6）提高手稿准备和赠款写作方面的技能。我们假设RA相关的炎症和不活动介导骨骼肌萎缩和腹部肥胖增加，这反过来又导致线粒体功能障碍和最终的胰岛素抵抗。这些假设将通过以下具体目的进行检验：1）确定与性别、年龄和BMI匹配的对照组相比，RA患者是否具有改变的身体组成和增加的脂解; 2）确定RA是否与参与肌肉萎缩的信号通路的高度激活和肌纤维组成的同步变化相关; 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受损的胰岛素信号传导;和，4）确定相对于性别、年龄和BMI匹配的对照，RA患者是否具有胰岛素抵抗，并评估RA患者胰岛素敏感性的预测因子，包括身体成分、脂解和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RA非药物治疗方法的创新假设，并实施一项全面的研究计划，旨在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.