Glucose Insulin and Muscle Loss

描述（由申请人提供）：Rita Kalyani 博士是约翰·霍普金斯大学医学院内分泌和代谢科的初级教员，她的临床实践致力于糖尿病的预防和治疗。她之前在约翰·霍普金斯大学公共卫生学院完成了临床研究健康科学硕士学位，在那里她运用流行病学和研究设计方面的培训来描述糖尿病与日常体力活动中的残疾之间的关系。在指导职业发展奖 (CDA) 的支持下，Kalyani 博士试图确定血糖异常和/或胰岛素抵抗 (IR) 在加速肌肉损失中的作用，以及当前糖尿病治疗方式（例如运动或胰岛素增敏药物）在减轻这些影响方面的作用。她还旨在更好地表征 2 型糖尿病中的骨骼肌线粒体功能障碍，将其作为将 IR 与随后的肌肉质量和力量损失联系起来的途径。 Kalyani 博士将 (1) 通过临床转化研究培训增强她的研究知识和技能，包括：试验管理、生物统计学、老年学、身体成分评估、骨骼肌生理学和高胰岛素正常血糖钳夹，(2) 接受由经验丰富的研究人员组成的跨学科团队的指导，(3) 沉浸在约翰霍普金斯大学糖尿病中心、韦尔奇流行病学、预防和治疗中心的研究和临床环境中。临床研究、约翰·霍普金斯运动生理学和身体成分核心、约翰·霍普金斯老龄化与健康中心以及校内国家老龄化研究所 - 临床研究分部。该 CDA 将为她提供成为 2 型糖尿病并发症加速肌肉损失的独立研究者所需的技能。基于她之前将功能结果应用于糖尿病研究的经验，她利用内分泌学、流行病学、老年学和运动生理学领域开发了一种新方法来理解和临床评估血糖异常和/或 IR 与肌肉损失的关系。在目标 1 中，她将使用两个已建立的数据集（一个横截面数据集和一个纵向数据集）来识别血糖异常的临床生物标志物和预测下肢肌肉质量和力量下降的 IR 指数。在目标 2 中，她将在一项将 6 个月运动训练干预与对照条件进行比较的试验中，确定运动减轻糖尿病患者肌肉损失的能力在多大程度上取决于现有的血糖异常或 IR 严重程度。在《目标 3》中，她 将招募未曾接受药物治疗的成人糖尿病患者参与一项新的临床研究，以调查口服药物如何 改善外周胰岛素敏感性的药物（吡格列酮），直接用钳夹评估，可以影响骨骼肌线粒体功能的不同但相关方面的变化（体外使用经皮肌肉活检和体内使用 31P 磁共振波谱）与安慰剂相比，以及效果是否因年龄而异。这些发现应该建立一个框架来评估现有糖尿病疗法保留肌肉的能力并可能确定新的治疗靶点。

DESCRIPTION (provided by applicant): Dr. Rita Kalyani is a junior faculty member in the Division of Endocrinology and Metabolism at the Johns Hopkins School of Medicine where her clinical practice is dedicated to the prevention and treatment of diabetes. She previously completed a Masters of Health Science in Clinical Investigation at the Johns Hopkins School of Public Health where she applied her training in epidemiology and study design to characterize the association of diabetes with disability in routine physical tasks. With the support of this Mentored Career Development Award (CDA), Dr. Kalyani seeks to establish the role of dysglycemia and/or insulin resistance (IR) in accelerated muscle loss and the role of current diabetes treatment modalities such as exercise or insulin-sensitizing medications in mitigating these effects. She also aims to better characterize skeletal muscle mitochondrial dysfunction in type 2 diabetes as a pathway connecting IR with subsequent loss of muscle mass and strength. Dr. Kalyani will (1) enhance her research knowledge and skills with training in clinical translatio research including: trial management, biostatistics, gerontology, body composition assessment, skeletal muscle physiology, and hyperinsulinemic-euglycemic clamp, (2) be mentored by an interdisciplinary team of experienced researchers, and (3) be immersed in the research and clinical environments of the Johns Hopkins Diabetes Center, the Welch Center for Epidemiology, Prevention and Clinical Research, the Johns Hopkins Exercise Physiology and Body Composition Core, the Johns Hopkins Center on Aging and Health, and intramural National Institute on Aging--Clinical Research Branch. This CDA will provide her with the skills she needs to become an independent investigator in accelerated muscle loss as a complication of type 2 diabetes. Building upon her prior experience in applying functional outcomes to diabetes research, she has developed a novel approach to understand and clinically assess the association of dysglycemia and/or IR with muscle loss that draws upon the fields of endocrinology, epidemiology, gerontology, and exercise physiology. In Aim 1, she will use two established datasets, one cross-sectional and one longitudinal, to identify clinical biomarkers of dysglycemia and indices of IR that predict decreased lower extremity muscle mass and strength. In Aim 2, she will determine the extent to which the ability of exercise to attenuate muscle loss in persons with diabetes depends upon the existing severity of dysglycemia or IR, in a trial comparing a 6 month exercise training intervention to a control condition. In Aim 3, she will recruit drug-naive adults with diabetes into a novel clinical study to investigate how an oral agent (pioglitazone) that improves peripheral insulin sensitivity, directly assessed with clamp, can effect changes in distinct but related aspects of skeletal muscle mitochondrial function--in vitro using percutaneous muscle biopsy and in vivo using 31P magnetic resonance spectroscopy-- versus placebo and whether effects differ by age. These findings should establish a framework to evaluate the ability of existing diabetes therapies to preserve muscle and potentially identify new therapeutic targets.