Unexpected Consequences of Insulin Resistance for the Heart

描述（由申请人提供）：我的近期目标是获得必要的技能和专业知识，以便在基础心血管研究的学术领域成功过渡到独立。这项工作的长期目标是提高我们对控制心脏中葡萄糖和脂肪酸利用的分子机制的认识。心血管疾病导致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有关，这两种物质都是为心脏提供能量的基质。与机体中其他对胰岛素有反应的组织一样，糖尿病患者的心脏也会产生胰岛素抵抗。由于胰岛素对葡萄糖摄取的损害是心肌胰岛素抵抗（MIR）的主要特征，我认为MIR是心脏保护自己免受糖尿病高血糖环境影响的适应性程序的一部分。其基本原理源于对心脏葡萄糖供应增加导致葡萄糖摄取速率大于细胞内葡萄糖氧化速率的观察

DESCRIPTION (provided by applicant): 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.