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：
7530481
负责人：
KIM M. HUFFMAN
金额：
$ 6.83万
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/7530481
关键词：
Abdomen Activities of Daily Living Address Adipose tissue Affect Age Apoptosis Arthritis Arts Atrophic Basic Science Biological Markers 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 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 Messenger RNA 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 Personal Satisfaction 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 Score Serine Serum Signal Pathway Signal Transduction Skeletal Muscle Skeletal system 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 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 men mitochondrial dysfunction mortality nutrition programs protein expression sedentary sex size skeletal stress 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）：类风湿性关节炎 (RA) 患者患心血管 (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，习惯性体力活动可以改善胰岛素作用和心血管发病率。运动给 RA 患者带来类似健康益处的潜力尚未被探索。该提案概述了职业培训和研究计划，该计划将为制定具体干预措施奠定基础，通过体育活动可用于调节 RA 的代谢性心血管风险。职业发展计划的重点是建立一个转化研究计划，应用最先进的技术对人类进行机械研究。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) 执行并熟练掌握骨骼肌活检技术； 3）发展运动生理学和身体活动干预方面的专业知识； 4) 培养临床试验设计和实施的技能，并获得负责任的研究行为的培训； 5）培养统计分析的高级技能； 6) 提高稿件准备和资助写作的技能。我们假设与 RA 相关的炎症和不活动会介导骨骼肌萎缩和腹部肥胖增加，进而导致线粒体功能障碍并最终导致胰岛素抵抗。这些假设将通过以下具体目标进行检验： 1) 确定与性别、年龄和 BMI 匹配的对照相比，类风湿性关节炎患者是否改变了身体成分并增加了脂肪分解； 2) 确定 RA 是否与参与肌肉萎缩的信号通路激活增强以及肌纤维组成的同时变化相关； 3) 确定 RA 患者的肌内脂质失衡和/或线粒体功能障碍是否会导致胰岛素信号传导受损； 4) 确定 RA 患者相对于性别、年龄和 BMI 匹配的对照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、脂肪分解和相关信号通路的激活肌肉萎缩和胰岛素脱敏。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，并实施一项综合研究计划，旨在加深我们对人类疾病机制的理解。