Unexpected Consequences of Insulin Resistance for the Heart

胰岛素抵抗对心脏的意外后果

• 批准号: 8985384
• 负责人: Romain Harmancey
• 金额: $ 24.07万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8985384
• 关键词: Address; Attenuated; Award; Biochemical; Calcium; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cells; Cessation of life; Chemicals; Chronic; Coronary artery; Development; Diabetes Mellitus; Energy Metabolism; Energy-Generating Resources; Ensure; Event; Failure; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Future; Gene Expression; Genes; Glucose; Glycolysis; Goals; Heart; Heart failure; Hepatic; Hexosamines; Hyperglycemia; Impairment; In Vitro; Insulin; Insulin Resistance; Investigation; Knowledge; Laboratories; Link; Mechanics; Mediating; Mediator of activation protein; Mentors; Metabolic; Metabolism; Modeling; Molecular; Molecular Biology; Myocardial; Myocardial Contraction; Non-Insulin-Dependent Diabetes Mellitus; Organism; Oxidative Stress; Pathway interactions; Pentosephosphate Pathway; Perception; Phase; Physiological; Poison; Poisoning; Process; Pump; Pyruvate; Research; Risk Factors; Signal Transduction; Skeletal Muscle; Stress; Techniques; Testing; Tissues; Work; Workload; base; biological adaptation to stress; blood glucose regulation; desensitization; design; disability; experience; fetal; glucose metabolism; glucose uptake; heart function; impaired capacity; improved; insulin signaling; mitochondrial uncoupling protein 3; novel; oxidation; premature; pressure; prevent; programs; protein degradation; response; skills; transcription factor

Summary My immediate goal is to acquire the necessary skills and expertise to make a successful transition to independence in the academic field of basic cardiovascular research. The long term goals of this work are to advance our knowledge on the molecular mechanisms that control glucose and fatty acid utilization in the heart. Premature death and disability from cardiovascular diseases are dire complications in diabetes. Diabetes is associated with high circulating levels of glucose and fatty acids, which are both energy providing substrates for the heart. Like other insulin-responsive tissues in the organism, the heart in diabetes becomes insulin resistant. Because impaired glucose uptake in response to insulin is the main feature of myocardial insulin resistance (MIR), I propose that MIR is part of an adaptive program with which the heart protects itself from the hyperglycemic milieu of diabetes mellitus. The rationale arises from the observation that increased glucose supply to the heart results in rates of glucose uptake greater than rates of glucose oxidation, the intracellular accumulation of glucose intermediates and, subsequently, contractile dysfunction. Specific Aim 1 will determine the effects of hyperglycemia on cardiac gene expression. This aim will test the hypothesis that the intracellular accumulation of glucose metabolites in the heart reactivates the fetal gene program, which can be prevented by the impairment of insulin-mediated glucose uptake. Specific Aim 2 will define the effect of MIR on energy metabolism and contractile function of the heart subjected to chronic pressure overload. Specifically, it will test the hypothesis that MIR increases glucose oxidation while limiting glucose uptake, and delays the transition toward failure of the stressed heart. Specific Aim 3 will seek to identify the molecular mechanism controlling substrate selection in the stressed heart. It will test the hypothesis that the uncoupling protein 3 (UCP3) decreases efficiency of the heart subjected to a high workload by inhibiting glucose oxidation. These aims will be addressed by combining my experience in molecular biology to the techniques available in the mentor’s laboratory, and will set the path to future investigations aiming to define the links between insulin signaling and the expression of UCP3 in the heart. Collectively, the proposed work seeks to demonstrate that MIR is more a physiological response for the stressed heart in diabetes, rather than a primary cause for heart failure.

概括 我的直接目标是获得必要的技能和专业知识，以成功过渡到 基本心血管研究学术领域的独立性。这项工作的长期目标是 促进我们对控制葡萄糖和脂肪酸利用的分子机制的了解 心。心血管疾病的过早死亡和残疾是糖尿病的严重并发症。 糖尿病与高循环水平的葡萄糖和脂肪酸相关，这些能量都提供 心脏的底物。像生物体中的其他胰岛素反应性组织一样，糖尿病中的心脏变成 胰岛素抵抗。因为响应胰岛素的葡萄糖摄取受损是心肌的主要特征 胰岛素抵抗（mir），我建议mir是一种自适应计划的一部分，心脏可以保护它 本身来自糖尿病高血糖环境。基本原理来自于观察到 增加的葡萄糖供应导致葡萄糖摄取速率大于葡萄糖氧化速率， 葡萄糖中间体的细胞内积累以及随后的收缩功能障碍。具体的 AIM 1将确定高血糖对心脏基因表达的影响。这个目标将检验假设 葡萄糖代谢产物在心脏中的细胞内积累重新激活了胎儿基因程序，该程序 胰岛素介导的葡萄糖摄取的损害可以预防。特定目标2将定义效果 MIR在能量代谢和心脏的收缩功能上受到慢性压力超负荷的影响。 具体而言，它将检验以下假设：MIR在限制葡萄糖摄取的同时增加葡萄糖氧化，并且 延迟了压力心脏失败的过渡。特定目标3将寻求识别分子 控制压力心脏中底物选择的机制。它将测试解开的假设 蛋白质3（UCP3）通过抑制葡萄糖氧化而降低了较高工作量的心脏效率。 这些目标将通过将我的分子生物学经验与可用的技术相结合来解决 精神的实验室，并将为未来的调查树立途径，以定义胰岛素之间的联系 信号传导和UCP3在心脏中的表达。拟议的工作总的来说，旨在证明 mir对糖尿病中压力的心脏的身体反应更多，而不是心脏的主要原因 失败。