Diet-Induced Insulin Resistance and Myocardial Ischemia in Pigs

饮食引起的猪胰岛素抵抗和心肌缺血

• 批准号: 7618190
• 负责人: GREGORY G SCHWARTZ
• 金额: $ 41.96万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-02-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7618190
• 关键词: 1-Phosphatidylinositol 3-Kinase; 2,4-thiazolidinedione; Acute myocardial infarction; Address; Affect; Agonist; Angina Pectoris; Animal Model; Animals; Atherosclerosis; Attenuated; Carbohydrates; Cardiac; Cardiolipins; Cardiovascular system; Cell Respiration; Chest; Chronic; Clinical; Complex; Condition; Country; Data; Development; Diabetes Mellitus; Diet; Exhibits; Family suidae; Fat-Restricted Diet; Fibrates; Functional disorder; Gene Expression; Gene Proteins; Genetic Models; Goals; Heart; Human; Infarction; Insulin; Insulin Resistance; Ischemia; Knowledge; Link; Lipids; Measurement; Metabolic; Metabolism; Modeling; Morbidity - disease rate; Myocardial; Myocardial Ischemia; Myocardial dysfunction; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Outcome; PPAR alpha; Pathologic; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Physiological reperfusion; Population; Recovery; Recovery of Function; Reperfusion Injury; Reperfusion Therapy; Rodent; Rodent Model; Signal Transduction; Sus scrofa; Testing; Thiazolidinediones; United States; Unstable angina; acute coronary syndrome; cardiovascular risk factor; fatty acid metabolism; feeding; insulin signaling; lipid metabolism; mortality; myocardial infarct sizing; outcome forecast; protein expression; pyruvate dehydrogenase; research study; response; saturated fat; size; sugar; tool

PROJECT SUMMARY: Two thirds of patients with acute myocardial infarction or unstable angina pectoris have underlying insulin resistance. Insulin resistance is an independent factor portending poor short and long-term prognosis in these patients. Hearts of insulin-resistant rodents exhibit abnormal carbohydrate and lipid metabolism that may be causally related to impaired functional recovery after ischemia and reperfusion (I/R). However, rodent models are limited by dissimilarities to human cardiac function, metabolism, and gene and protein expression. A large animal model of insulin resistance would be an important tool in bridging rodent and human pathophysiology in this condition. This study will test the hypothesis that diet-induced insulin resistance in pigs causes pathologic alterations of myocardial carbohydrate and lipid metabolism that adversely affect the response to I/R. Pigs fed a diet high in saturated fat and simple sugars develop obesity and insulin resistance over several months; they are compared to lean controls fed a low-fat diet with no added sugar. Under anesthetized, open-chest conditions, pigs undergo low-flow myocardial I/R with concomitant measurements of cardiac contractile function, substrate utilization, and gene expression. Experiments will determine whether diminished recovery of contractile function in insulin-resistant pigs is related to myocardial insulin resistance due to impaired signaling through the phosphatidylinositol-3-kinase pathway, decreased activity of pyruvate dehydrogenase, altered myocardial free fatty acid metabolism and/or lipid accumulation, or alterations of cardiolipin content and composition. Peroxisome proliferator-activated receptors (PPARs) are critical regulators of substrate metabolism whose expression and function in myocardium may be altered by insulin resistance. Moreover, many patients with insulin resistance are treated with PPAR agonist drugs (fibrates, thiazolidinediones) despite little knowledge of their cardiac effects. Therefore, an additional goal is to determine whether chronic treatment with a PPAR alpha or gamma agonist modifies myocardial metabolic and contractile dysfunction after I/R in insulin resistant pigs.

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