Glucose Insulin and Muscle Loss

葡萄糖胰岛素和肌肉损失

• 批准号: 8538962
• 负责人: Rita R Kalyani
• 金额: $ 15.87万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538962
• 关键词: Adult; Adverse effects; Aerobic; Affect; Age; Aging; Area Under Curve; Attenuated; Baltimore; Behavioral; Biological Markers; Biometry; Biopsy; Body Composition; Chronic; Clinical; Clinical Research; Clinical Trials; Communities; Complication; Cross-Sectional Studies; Data; Data Analyses; Data Set; Diabetes Mellitus; Dose; Educational Intervention; Electron Microscopy; Electron Transport; Endocrinology; Enrollment; Environment; Epidemiologic Studies; Epidemiology; Euglycemic Clamping; Exercise; Exercise Physiology; Faculty; Fasting; Future; General Population; Gerontology; Glucose; Glucose Clamp; Glycosylated hemoglobin A; Goals; Health; Health Sciences; Homeostasis; In Vitro; Insulin; Insulin Resistance; Intervention; K-Series Research Career Programs; Knowledge; Lead; Leg; Longitudinal Studies; Lower Extremity; Magnetic Resonance Spectroscopy; Measurement; Measures; Mentors; Metabolism; Methods; Mitochondria; Modality; Modeling; Modification; Morbidity - disease rate; Morphology; Muscle; National Health and Nutrition Examination Survey; National Institute on Aging; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Oral; PPAR gamma; Pathway interactions; Patients; Peripheral; Persons; Pharmaceutical Preparations; Physiology; Pioglitazone; Placebos; Population; Prediabetes syndrome; Prevalence; Prevention; Prevention Research; Production; Public Health; Public Health Schools; Randomized; Recruitment Activity; Research; Research Design; Research Infrastructure; Research Personnel; Resolution; Resources; Role; Severities; Skeletal Muscle; Surrogate Markers; Testing; Therapeutic; Training; United States National Institutes of Health; Visit; base; clinical practice; cohort; cost; density; diabetes mellitus therapy; disability; effective therapy; epidemiology study; experience; fasting glucose; functional outcomes; glucose metabolism; improved; in vivo; indexing; inorganic phosphate; insight; insulin sensitivity; insulin sensitizing drugs; medical schools; member; mitochondrial dysfunction; mortality; muscle form; muscle strength; new therapeutic target; novel; novel strategies; response; skills; therapeutic development; treatment as usual; trial comparing; vastus lateralis

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.

描述（由申请人提供）：Rita Kalyani博士是约翰霍普金斯医学院内分泌和代谢科的初级教员，她的临床实践致力于预防和治疗糖尿病。她之前在约翰霍普金斯公共卫生学院完成了临床调查健康科学硕士学位，在那里她应用她在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劳动中残疾的关联。在这个指导职业发展奖（CDA）的支持下，Kalyani博士寻求建立功能障碍和/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）在减轻这些影响中的作用。她还旨在更好地描述2型糖尿病中骨骼肌线粒体功能障碍的特征，将其作为连接IR与随后肌肉质量和力量损失的途径。Kalyani博士将（1）通过临床药理学研究培训提高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）由经验丰富的研究人员组成的跨学科团队指导，（3）沉浸在约翰霍普金斯糖尿病中心的研究和临床环境中，韦尔奇流行病学、预防和临床研究中心、约翰霍普金斯运动生理学和身体成分中心、约翰霍普金斯老龄化与健康中心和国家老龄化研究所--临床研究分支。该CDA将为她提供所需的技能，使她成为2型糖尿病并发症加速肌肉损失的独立研究者。基于她以前将功能结局应用于糖尿病研究的经验，她开发了一种新的方法来了解和临床评估功能障碍和/或IR与肌肉损失的关联，该方法借鉴了内分泌学，流行病学，老年学和运动生理学领域。在目标1中，她将使用两个已建立的数据集，一个是横截面数据集，一个是纵向数据集，以确定功能障碍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，她将在一项比较6个月运动训练干预与对照条件的试验中，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糖尿病或IR的现有严重程度。在目标3中，她 将招募未接受过药物治疗的糖尿病成年人参加一项新的临床研究， 与安慰剂相比，用钳夹直接评估的改善外周胰岛素敏感性的药物（吡格列酮）可以影响骨骼肌线粒体功能的不同但相关的方面的变化-体外使用经皮肌肉活检和体内使用31 P磁共振光谱-以及影响是否因年龄而异。这些发现应该建立一个框架，以评估现有糖尿病治疗方法保护肌肉的能力，并可能确定新的治疗靶点。