Mechanisms of Insulin Resistance in Rheumatoid Arthritis

类风湿关节炎的胰岛素抵抗机制

基本信息

批准号：
8123308
负责人：
KIM M. HUFFMAN
金额：
$ 7.23万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-05 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8123308
关键词：
3 year old Abdomen Activities of Daily Living Address Adipose tissue Affect Age Apoptosis Arthritis Atrophic Basic Science Biopsy Body Composition Body mass index C-reactive protein Cardiovascular Diseases Cardiovascular system Central obesity Chronic Citrate (si)-Synthase Clinic Clinical Trials Clinical Trials Design Complex Data Data Analyses Development Plans Diagnostic Disease Disease Management Disease Resistance Exercise Exercise Physiology Facilities and Administrative Costs Fatty Acids Fiber Functional disorder Gender General Population Glycerol Goals Grant Health Health Benefit Human Individual Inflammation Inflammatory Insulin Insulin Resistance Intervention Intramuscular Investigation Knowledge Laboratories Lead Lipids Lipolysis Manuscripts Measurement Measures Mediating Metabolic Metabolism Mitochondria Molecular Morbidity - disease rate Muscle Muscle Fibers Muscle function Muscular Atrophy Nonesterified Fatty Acids Obesity Outcome Pathway interactions Patient Self-Report Patients Persons Phenotype Phosphorylation Physical activity Physiology Plasma Population Population Study Preparation Proteins Qualifying Relative (related person)Research Research Infrastructure Research Personnel Research Training Resources Rheumatoid Arthritis Ring Finger Domain Risk Factors Role Serine Serum Signal Pathway Signal Transduction Skeletal Muscle Stress Techniques Technology Testing Thigh structure Tissues Training Translational Research Ubiquitin Visceral Woman Work Writing X-Ray Computed Tomography base cardiovascular disorder prevention cardiovascular disorder risk cardiovascular risk factor career career development cytokine density desensitization disability experience fatty acid metabolism human disease improved indexing innovation insulin receptor substrate 1 protein insulin sensitivity insulin signaling intravenous glucose tolerance test mRNA Expression men mitochondrial dysfunction molecular marker mortality muscle form nutrition programs protein expression responsible research conduct sedentary sex skeletal muscle wasting skills skills training subcutaneous wasting

项目摘要

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.

描述（由申请人提供）：类风湿关节炎（RA）患者患心血管疾病（CV）疾病和胰岛素抵抗的风险增加，这是代谢性CV风险因素。在没有RA的个体中，习惯性体育锻炼可改善胰岛素作用和CV发病率。尚未探索运动赋予RA患者类似健康益处的潜力。该提案概述了职业培训和研究计划，该计划将为开发特定干预措施提供基础，从而将体育活动可用于调节RA中的代谢简历风险。职业发展计划的重点是构建一项翻译研究计划，该计划应用最先进的技术在人群中进行机械研究。该计划的目标如下：1）发展与新陈代谢相关的培训和技能； 2）表现并熟练掌握骨骼肌肉活检技术； 3）发展运动生理和体育锻炼干预方面的专业知识； 4）发展临床试验设计和实施技能，并获得负责任的研究的培训； 5）在统计分析中发展高级技能； 6）提高手稿准备和授予写作技能。我们假设RA相关的炎症和不活跃介导骨骼肌萎缩并增加腹部肥胖，这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特定目的进行测试：1）确定与性别，年龄和BMI匹配对照相比，患有RA的人是否改变了身体成分和脂解的增加； 2）确定RA是否与肌肉浪费涉及的信号通路的激活增加以及肌肉纤维组成的一致变化相关； 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胰岛素信号受损；和4）确定与性别，年龄和BMI匹配的对照相对于RA的患者是否具有胰岛素耐药性，并评估RA患者中胰岛素敏感性的预测因子，包括身体组成，脂解，以及与肌肉浪费和胰岛素脱发有关的信号传导途径的激活。因此，这项工作将探讨适用于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。