Diet-Induced Insulin Resistance and Myocardial Ischemia in Pigs

描述（由申请人提供）：三分之二的急性心肌梗死或不稳定型心绞痛患者存在潜在的胰岛素抵抗。胰岛素抵抗是一个独立的因素，预示着这些患者的短期和长期预后不良。胰岛素抵抗啮齿动物的心脏表现出异常的碳水化合物和脂质代谢，这可能与缺血和再灌注（I/R）后功能恢复受损有因果关系。然而，啮齿动物模型受到与人类心脏功能、代谢以及基因和蛋白质表达不同的限制。胰岛素抵抗的大型动物模型将是在这种情况下桥接啮齿动物和人类病理生理学的重要工具。本研究将检验猪饮食诱导的胰岛素抵抗导致心肌碳水化合物和脂质代谢病理改变，从而对I/R反应产生不利影响的假设。喂食高饱和脂肪和单糖饮食的猪在几个月内会出现肥胖和胰岛素抵抗;他们与喂食低脂饮食而不添加糖的瘦对照组进行比较。在麻醉条件下，对猪进行心肌I/R，同时测量心脏收缩功能和底物代谢。实验将确定胰岛素抵抗猪的收缩功能恢复减弱是否与心肌胰岛素抵抗有关，这是由于磷脂酰肌醇-3-激酶途径的信号传导受损、丙酮酸脱氢酶活性降低、心肌游离脂肪酸代谢和/或脂质蓄积改变或心磷脂含量和组成改变所致。过氧化物酶体增殖物激活受体（PPARs）是重要的底物代谢调节因子，胰岛素抵抗可改变PPARs在心肌中的表达和功能。此外，许多胰岛素抵抗患者接受PPAR激动剂药物（贝特类、噻唑烷二酮类）治疗，尽管对它们的心脏效应知之甚少。因此，另一个目标是确定是否与PPAR α或γ激动剂慢性治疗改变胰岛素抵抗猪心肌代谢和收缩异常。

DESCRIPTION (provided by applicant): 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 conditions, pigs are subjected to myocardial I/R with concomitant measurements of cardiac contractile function, and substrate metabolism. 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 abnormalities in insulin resistant pigs.