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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：
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
项目类别：
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

项目摘要

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.

总结