Unexpected Consequences of Insulin Resistance for the Heart

胰岛素抵抗对心脏的意外后果

基本信息

批准号：
8704769
负责人：
Romain Harmancey
金额：
$ 8.87万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-22 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8704769
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

项目摘要

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.

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心脏中葡萄糖和脂肪酸利用的分子机制的了解。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，它们都是为心脏提供底物的能量。像生物体中的其他胰岛素反应性组织一样，糖尿病中的心脏变得抗胰岛素。由于响应胰岛素的葡萄糖摄取受损是心肌胰岛素抵抗（MIR）的主要特征，因此我认为MIR是一种适应性程序的一部分，心脏可以保护自己免受糖尿病高血糖环境的影响。基本原理是由于观察到增加的葡萄糖供应增加导致葡萄糖摄取率大于葡萄糖氧化速率，细胞内细胞内葡萄糖中间体的积累，随后是收缩功能障碍。具体目标1将确定高血糖对心脏基因表达的影响。该目标将检验以下假设：心脏中葡萄糖代谢产物的细胞内积累重新激活了胎儿基因程序，这可以通过胰岛素介导的葡萄糖摄取受损而预防。特定的目标2将定义MIR对经慢性压力超负荷的心脏能量代谢和收缩功能的影响。具体而言，它将检验以下假设：MIR在限制葡萄糖吸收的同时增加葡萄糖氧化，并延迟向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。它将检验以下假设：解耦蛋白3（UCP3）通过抑制葡萄糖氧化而降低了受高度工作量的心脏效率。这些目标将通过将我在分子生物学的经验与导师实验室中可用的技术相结合，并将为未来的研究提供旨在定义胰岛素信号传导与心脏中UCP3表达之间的联系的途径。总的来说，拟议的工作试图证明MIR对糖尿病中压力性心脏的生理反应更多，而不是心力衰竭的主要原因。