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: 7845092
• 负责人: GREGORY G SCHWARTZ
• 金额: $ 46.99万
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7845092
• 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; Chronic; Clinical; Complex; Country; Data; Development; Diabetes Mellitus; Diet; Exhibits; Family suidae; Fat-Restricted Diet; Fatty acid glycerol esters; Fibrates; Functional disorder; Gene Proteins; Genetic Models; Goals; Heart; Hormones; Human; Infarction; Insulin; Insulin Resistance; Ischemia; Knowledge; Left; Left Ventricular Remodeling; Link; Lipids; Measurement; Metabolic; Metabolism; Modeling; Morbidity - disease rate; Myocardial; Myocardial Infarction; 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; Population; Prediabetes syndrome; Recovery; Recovery of Function; Reperfusion Injury; Reperfusion Therapy; Resistance; Rodent; Rodent Model; Signal Transduction; Testing; Thiazolidinediones; United States; Unstable angina; Ventricular; acute coronary syndrome; cardiovascular risk factor; fatty acid metabolism; feeding; insulin signaling; lipid metabolism; mortality; myocardial infarct sizing; outcome forecast; protein expression; public health relevance; pyruvate dehydrogenase; research study; response; saturated fat; sugar; tool

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. PUBLIC HEALTH RELEVANCE: Patients with type 2 diabetes or "prediabetes" are resistant to the effects of the hormone insulin. Patients with insulin resistance have a poor prognosis after heart attack. Using pigs, this study will determine the ways in which the use of sugars and fats by the heart is altered in insulin resistance, leading to poorer cardiac function after heart attack.

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有潜在的胰岛素抵抗。胰岛素抵抗是预示这些患者短期和长期预后不良的独立因素。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、基因和蛋白质表达差异的限制。胰岛素抵抗的大型动物模型将是在这种情况下连接啮齿动物和人类病理生理的重要工具。本研究将验证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的病理改变，从而对I/R反应产生不利影响的假设。饲粮中富含饱和脂肪和单糖的猪在几个月后会出现肥胖和胰岛素抵抗；研究人员将他们与不添加糖的低脂饮食进行比较。在麻醉条件下，猪接受心肌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收缩功能恢复的减弱是否与心肌胰岛素抵抗有关，原因是磷脂酰肌醇-3激酶信号通路受损、丙酮酸脱氢酶活性降低、心肌游离脂肪酸代谢和/或脂质积累改变，或心磷脂含量和组成改变。过氧化物酶体增殖物激活受体（PPARs）是底物代谢的关键调节因子，其在心肌中的表达和功能可能因胰岛素抵抗而改变。此外，许多胰岛素抵抗患者使用PPAR激动剂（贝特类，噻唑烷二酮类）治疗，尽管对其心脏作用知之甚少。因此，另一个目标是确定PPAR α或γ激动剂的慢性治疗是否会改变胰岛素抵抗猪的心肌代谢和收缩异常。公共卫生相关性：2型糖尿病或“前驱糖尿病”患者对激素胰岛素的作用有抵抗性。胰岛素抵抗患者心脏病发作后预后较差。在猪身上，这项研究将确定心脏对糖和脂肪的使用在胰岛素抵抗中是如何改变的，从而导致心脏病发作后心脏功能变差。