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

基本信息

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
项目类别：
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

项目摘要

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塞或不稳定的心绞痛患者具有潜在的胰岛素抵抗。胰岛素抵抗是这些患者的独立因素，这些因素可以预期短期和长期预后。耐胰岛素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后的功能恢复受损有关（I/R）。但是，啮齿动物模型受到与人心脏功能，代谢以及基因和蛋白质表达的差异的限制。在这种情况下，胰岛素抵抗的大型动物模型将是桥接啮齿动物和人类病理生理学的重要工具。这项研究将检验以下假设：饮食诱导的猪胰岛素抵抗会导致心肌碳水化合物和脂质代谢的病理改变，从而不利地影响对I/R的反应。饲喂高饱和脂肪和简单糖的饮食的猪会在几个月内产生肥胖和胰岛素耐药性。将它们与富含低脂饮食的瘦对手进行比较，没有添加糖。在麻醉条件下，猪会接受心肌I/R，并具有对心脏收缩功能和底物代谢的伴随测量。实验将确定在胰岛素耐药性猪中收缩功能的恢复是否减少，这与通过磷脂酰肌醇-3-激酶途径的信号传导受损引起的心肌胰岛素耐药性有关，丙酮酸脱氢酶的活性降低，降低了心肌酸性脂肪酸性化代谢和脂肪累积，或者累积的脂肪酸脂肪酸性累积，或者的组成改变了反应型contrimip and contrimip and contrumation contrumation contrumation contemutiation contemutiation contemutiation累积。过氧化物酶体增殖物激活受体（PPAR）是底物代谢的关键调节剂，其在心肌中的表达和功能可能会因胰岛素抵抗而改变。此外，尽管对他们的心脏作用知之甚少，但许多胰岛素抵抗性患者都接受了PPAR激动剂药物（纤维化，噻唑烷二酮）的治疗。因此，另一个目标是确定使用PPARα或伽马激动剂的慢性治疗是否会修饰抗胰岛素耐药猪的心肌代谢异常和收缩异常。公共卫生相关性：2型糖尿病或“糖尿病前期”患者对激素胰岛素的作用有抵抗力。胰岛素抵抗患者心脏病发作后预后不良。使用猪，这项研究将确定胰岛素抵抗改变心脏糖和脂肪的使用方式，从而导致心脏病发作后心脏功能较差。