Glucose Insulin and Muscle Loss

描述(由申请人提供)：丽塔·卡利亚尼博士是约翰霍普金斯大学医学院内分泌学和新陈代谢系的初级教员，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调查健康科学硕士学位，在那里她应用了流行病学和研究设计方面的培训，以确定糖尿病与日常体力任务中残疾的关联。在这项指导职业发展奖(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(如运动或胰岛素增敏药物)在缓解这些影响方面的作用。她还致力于更好地描述2型糖尿病患者骨骼肌线粒体功能障碍的特征，以此作为连接IR与随后的肌肉质量和力量丧失的途径。Kalyani博士将(1)通过临床翻译研究培训来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，(2)由经验丰富的研究人员组成的跨学科团队指导，以及(3)沉浸在约翰霍普金斯糖尿病中心、韦尔奇流行病学、预防和临床研究中心、约翰霍普金斯大学运动生理学和身体成分核心中心、约翰霍普金斯大学老龄化与健康中心和大学内部老龄化与临床研究所的研究和临床环境中。这一CDA将为她提供所需的技能，使她成为作为2型糖尿病并发症的加速肌肉损失的独立调查者。在将功能结果应用于糖尿病研究方面的经验基础上，她开发了一种新的方法，利用内分泌学、流行病学、老年学和运动生理学等领域，了解和临床评估血糖异常和/或IR与肌肉损失的关联。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，以确定血糖紊乱的临床生物标记物和预测腿部肌肉质量和力量减少的IR指数。在目标2中，她将在一项比较6个月运动训练干预和对照条件的试验中，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紊乱或IR的严重程度。在《目标3》中，她 将招募患有糖尿病的未服用药物的成年人进行一项新的临床研究，以调查口服 使用钳夹直接评估改善外周胰岛素敏感性的药物(吡格列酮)与安慰剂相比，可以影响骨骼肌线粒体功能的不同但相关方面的变化--体外使用经皮肌活检和体内使用31P磁共振波谱-以及效果是否因年龄而不同。这些发现应该建立一个框架，以评估现有糖尿病疗法保护肌肉的能力，并潜在地确定新的治疗靶点。

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.