Oxidative Capacity, Lipid Partitioning and Insulin Resistance in Skeletal Muscle

骨骼肌的氧化能力、脂质分配和胰岛素抵抗

• 批准号: 8132813
• 负责人: JOHN J DUBE
• 金额: $ 12.49万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8132813
• 关键词: 1,2-diacylglycerol; Acute; Address; Adipocytes; Aerobic Exercise; Affect; Animal Model; Animals; Area; Basic Science; Belief; Biological Models; Biopsy; Biopsy Specimen; Cell Culture Techniques; Cell Respiration; Cells; Ceramides; Chronic; Clinical Research; Clinical Trials; Collaborations; Data; Development; Diabetes Mellitus; Diglycerides; Endocrinology; Euglycemic Clamping; Exercise; Exposure to; Fatty Acids; Foundations; Future; Gene Expression; Glucose Clamp; Glycogen; Goals; Human; Hypertriglyceridemia; In Vitro; Incubated; Infusion procedures; Institution; Insulin; Insulin Resistance; Investigation; Kentucky; Lead; Lipase; Lipids; Mass Spectrum Analysis; Mediating; Mentors; Methodology; Methods; Mitochondria; Muscle; Muscle Cells; Myoblasts; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Pharmacology; Primary Cell Cultures; Proteins; Research; Research Design; Research Methodology; Research Personnel; Research Scientist Award; Role; Saturated Fatty Acids; Scientist; Skeletal Muscle; Staging; Techniques; Testing; Training; Translational Research; Triglycerides; United States National Institutes of Health; Universities; Unsaturated Fatty Acids; Western Blotting; adipocyte differentiation; aged; career; career development; clinically relevant; diet and exercise; experience; fatty acid oxidation; glucose disposal; glucose uptake; improved; in vivo; insulin sensitivity; insulin signaling; multidisciplinary; novel; prevent; programs; protein expression; public health relevance; research and development; sedentary; translational approach; volunteer

DESCRIPTION (provided by applicant): This is a five-year career development and research program to study mechanisms associated with lipid induced insulin resistance. The overall objective of this proposal is to determine the effects of lipid oversupply on lipid partitioning, mitochondrial capacity and insulin sensitivity within human skeletal muscle. I will complete the proposed career development and research program primarily at the Division of Endocrinology of the University of Pittsburgh under the direction of Dr. Bret Goodpaster. I will receive extensive training in clinical research methods and design as well as specific training with methods to assess insulin resistance in vivo and protein and gene expression in human muscle biopsy specimens. I will receive training in primary myocyte culture methodology under the direction of Dr. Charlotte Peterson at the University of Kentucky. Training in mass spectroscopy determination of skeletal muscle lipids will take place under the direction of Drs. Paul Baker and Bruce Freemen in the Department of Pharmacology at the University of Pittsburgh. This specific theoretic and practical training is directly related to my future plans to conduct obesity and diabetes research. More broadly, these experiences will build upon a foundation of basic science and clinical research and aid in my development as an independent translational scientist. My preliminary data suggests that aerobic exercise alters skeletal muscle lipid partitioning (increased triglycerides but lower diacylglycerol and ceramides) and these changes may be related to perturbations in lipid droplet proteins and enhanced mitochondrial content and/or capacity. Within this proposed period of training, I intend to extend this line of research to explore the possibility that alterations in the fatty acid composition of various lipid species (triglyceride, diacylglycerol and ceramide) may be causative in lipotoxic mediated insulin resistance. Acute in vivo studies of lipid oversupply, together with human primary cell culture techniques, will also be utilized to further explore pathways mediating improved insulin resistance, including mitochondrial capacity and changes in lipid droplet gene and protein expression. Supplemented by collaborations outside my primary Institution, the University of Pittsburgh is an ideal setting for me to develop professionally and begin a successful career as an independent translational research scientist. PUBLIC HEALTH RELEVANCE: I will study how too much lipid exposure to muscle may lead to the development of insulin resistance, a primary cause of type 2 diabetes. These studies will help us better understand the way in which exercise and diet can prevent or treat type 2 diabetes.

描述（由申请人提供）：这是一个五年的职业发展和研究计划，用于研究与脂质诱导的胰岛素抵抗相关的机制。该提案的总体目的是确定脂质过度供应对人骨骼肌内脂质分配，线粒体能力和胰岛素敏感性的影响。 我将在Bret Goodpaster博士的指导下，主要在匹兹堡大学内分泌学部门完成拟议的职业发展和研究计划。我将接受有关临床研究方法和设计的广泛培训，以及通过评估人体肌肉活检标本中胰岛素耐药性的特定培训。在肯塔基大学夏洛特·彼得森（Charlotte Peterson）博士的指导下，我将接受一级肌细胞培养方法的培训。骨骼肌脂质的质谱测定训练将在DRS的指导下进行。匹兹堡大学药理学系的Paul Baker和Bruce Freemen。这种特定的理论和实用培训与我未来进行肥胖和糖尿病研究的计划直接相关。从更广泛的角度来看，这些经验将基于基础科学和临床研究的基础，并帮助我作为独立翻译科学家的发展。 我的初步数据表明，有氧运动改变了骨骼肌脂质分配（甘油三酸酯增加，但二酰基甘油和神经酰胺较低），这些变化可能与脂质液滴蛋白的扰动以及增强的线粒体含量和/或能力有关。在拟议的训练期内，我打算扩展这一研究线，以探讨各种脂质物种（甘油三酸酯，二酰基甘油和神经酰胺）的脂肪酸组成的改变可能在脂蛋白毒性介导的胰岛素耐药性中是可取的。脂质过度供应的急性体内研究以及人类原代细胞培养技术也将用于进一步探索介导胰岛素耐药性改善的途径，包括线粒体能力以及脂质液滴基因和蛋白质表达的变化。 匹兹堡大学在我的主要机构之外的合作中得到补充，是我专业发展并开始成功地成为独立翻译研究科学家的理想场所。 公共卫生相关性：我将研究脂质暴露于肌肉中如何导致胰岛素抵抗的发展，胰岛素抵抗是2型糖尿病的主要原因。这些研究将帮助我们更好地了解运动和饮食可以预防或治疗2型糖尿病的方式。