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.

项目概要： 三分之二的急性心肌梗塞或不稳定型心绞痛患者患有 潜在的胰岛素抵抗。胰岛素抵抗是预示身体状况不佳的独立因素 这些患者的短期和长期预后。胰岛素抵抗啮齿类动物的心脏 表现出异常的碳水化合物和脂质代谢，可能与 缺血再灌注（I/R）后功能恢复受损。然而，啮齿动物 模型受到人类心脏功能、新陈代谢和基因差异的限制 和蛋白质表达。胰岛素抵抗的大型动物模型将是一个重要的 在这种情况下桥接啮齿动物和人类病理生理学的工具。这项研究将测试 饮食诱导的猪胰岛素抵抗导致病理改变的假设 心肌碳水化合物和脂质代谢对反应产生不利影响 I/R。饲喂高饱和脂肪和单糖饮食的猪会出现肥胖和胰岛素升高 抵抗数月；将他们与低脂饮食的瘦对照进行比较 不添加糖。在麻醉、开胸条件下，猪经历低流量 心肌 I/R 并同时测量心脏收缩功能、底物 利用和基因表达。实验将确定是否减少 胰岛素抵抗猪收缩功能的恢复与心肌胰岛素有关 由于磷脂酰肌醇-3-激酶途径信号传导受损而产生耐药性， 丙酮酸脱氢酶活性降低，心肌游离脂肪酸改变 代谢和/或脂质积累，或心磷脂含量的改变和 作品。过氧化物酶体增殖物激活受体 (PPAR) 是关键的调节因子 心肌中表达和功能可能发生改变的底物代谢 通过胰岛素抵抗。此外，许多患有胰岛素抵抗的患者接受以下治疗： PPAR 激动剂药物（贝特类、噻唑烷二酮类）尽管对其心脏功能知之甚少 影响。因此，另一个目标是确定慢性治疗是否 PPAR α 或 γ 激动剂改变心肌代谢和收缩 胰岛素抵抗猪 I/R 后功能障碍。