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:7618190
- 负责人:
- 金额:$ 41.96万
- 依托单位:
- 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 2009-05-31
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-Kinase2,4-thiazolidinedioneAcute myocardial infarctionAddressAffectAgonistAngina PectorisAnimal ModelAnimalsAtherosclerosisAttenuatedCarbohydratesCardiacCardiolipinsCardiovascular systemCell RespirationChestChronicClinicalComplexConditionCountryDataDevelopmentDiabetes MellitusDietExhibitsFamily suidaeFat-Restricted DietFibratesFunctional disorderGene ExpressionGene ProteinsGenetic ModelsGoalsHeartHumanInfarctionInsulinInsulin ResistanceIschemiaKnowledgeLinkLipidsMeasurementMetabolicMetabolismModelingMorbidity - disease rateMyocardialMyocardial IschemiaMyocardial dysfunctionMyocardiumNon-Insulin-Dependent Diabetes MellitusNonesterified Fatty AcidsObesityOutcomePPAR alphaPathologicPathway interactionsPatientsPeroxisome Proliferator-Activated ReceptorsPharmaceutical PreparationsPhysiological reperfusionPopulationRecoveryRecovery of FunctionReperfusion InjuryReperfusion TherapyRodentRodent ModelSignal TransductionSus scrofaTestingThiazolidinedionesUnited StatesUnstable anginaacute coronary syndromecardiovascular risk factorfatty acid metabolismfeedinginsulin signalinglipid metabolismmortalitymyocardial infarct sizingoutcome forecastprotein expressionpyruvate dehydrogenaseresearch studyresponsesaturated fatsizesugartool
项目摘要
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.
项目总结:
三分之二的急性心肌梗死或不稳定型心绞痛患者
潜在的胰岛素抵抗。胰岛素抵抗是预示不良的一个独立因素
这些患者的近期和远期预后。胰岛素抵抗啮齿动物的心脏
表现出碳水化合物和脂肪代谢异常,可能与
缺血再灌流(I/R)后功能恢复受损。然而,啮齿动物
模型受限于与人类心脏功能、新陈代谢和基因的不同。
和蛋白质的表达。一个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,在啮齿动物和人类病理生理学之间架起桥梁的工具。这项研究将测试
饮食诱导的猪胰岛素抵抗引起病理改变的假说
对心肌碳水化合物和脂肪代谢产生不利影响的
I/R喂食高饱和脂肪和单糖的猪会出现肥胖和胰岛素
几个月的抵抗力;他们与喂食低脂肪饮食的瘦肉型对照组进行比较
不加糖。在麻醉的开胸条件下,猪经历低流量
心肌I/R伴随心脏收缩功能的测量底物
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
由于通过磷脂酰肌醇-3-激酶途径的信号受损而产生的耐药性,
丙酮酸脱氢酶活性降低,心肌游离脂肪酸改变
代谢和/或脂质堆积,或心磷脂含量和
组成。过氧化物酶体增殖物激活受体(PPAR)是重要的调节因子
其在心肌中的表达和功能可能发生改变的底物代谢
由胰岛素抵抗引起。此外,许多患有胰岛素抵抗的患者都被用来治疗
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
效果。因此,另一个目标是确定慢性药物治疗是否
PPARα或伽马激动剂改变心肌代谢和收缩
胰岛素抵抗猪的I/R后功能障碍。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)
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GREGORY G SCHWARTZ其他文献
GREGORY G SCHWARTZ的其他文献
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{{ truncateString('GREGORY G SCHWARTZ', 18)}}的其他基金
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:
8069630 - 财政年份:1994
- 资助金额:
$ 41.96万 - 项目类别:
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 - 财政年份:1994
- 资助金额:
$ 41.96万 - 项目类别:
Protection by Thiazolidinediones in Myocardial Ischemia
噻唑烷二酮类药物对心肌缺血的保护作用
- 批准号:
6604250 - 财政年份:1994
- 资助金额:
$ 41.96万 - 项目类别:
Protection by Thiazolidinediones in Myocardial Ischemia
噻唑烷二酮类药物对心肌缺血的保护作用
- 批准号:
6436621 - 财政年份:1994
- 资助金额:
$ 41.96万 - 项目类别:
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:
8280242 - 财政年份:1994
- 资助金额:
$ 41.96万 - 项目类别:
Protection by Thiazolidinediones in Myocardial Ischemia
噻唑烷二酮类药物对心肌缺血的保护作用
- 批准号:
7087019 - 财政年份:1994
- 资助金额:
$ 41.96万 - 项目类别: