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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Myocardial Ischemia and Metabolism Study Section (MIM)
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Schwartz, Lisa
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University of Colorado Denver
Internal Medicine/Medicine
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United States
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Huang, Janice V; Lu, Li; Ye, Shuyu et al. (2013) Impaired contractile recovery after low-flow myocardial ischemia in a porcine model of metabolic syndrome. Am J Physiol Heart Circ Physiol 304:H861-73
Low Wang, Cecilia C; Lu, Li; Leitner, J Wayne et al. (2013) Arterial insulin resistance in Yucatan micropigs with diet-induced obesity and metabolic syndrome. J Diabetes Complications 27:307-15
Sarraf, Mohammad; Lu, Li; Ye, Shuyu et al. (2012) Thiazolidinedione drugs promote onset, alter characteristics, and increase mortality of ischemic ventricular fibrillation in pigs. Cardiovasc Drugs Ther 26:195-204
Ahmad, Hasan A; Lu, Li; Ye, Shuyu et al. (2012) Calpain inhibition preserves talin and attenuates right heart failure in acute pulmonary hypertension. Am J Respir Cell Mol Biol 47:379-86
Huang, Janice V; Greyson, Clifford R; Schwartz, Gregory G (2012) PPAR-? as a therapeutic target in cardiovascular disease: evidence and uncertainty. J Lipid Res 53:1738-54
Lee, Jenny; Xu, Ya; Lu, Li et al. (2010) Multiple abnormalities of myocardial insulin signaling in a porcine model of diet-induced obesity. Am J Physiol Heart Circ Physiol 298:H310-9
Xu, Ya; Lu, Li; Greyson, Clifford et al. (2006) The PPAR-alpha activator fenofibrate fails to provide myocardial protection in ischemia and reperfusion in pigs. Am J Physiol Heart Circ Physiol 290:H1798-807
Xu, Ya; Gen, Michael; Lu, Li et al. (2005) PPAR-gamma activation fails to provide myocardial protection in ischemia and reperfusion in pigs. Am J Physiol Heart Circ Physiol 288:H1314-23
Xu, Ya; Lu, Li; Greyson, Clifford et al. (2003) Deleterious effects of acute treatment with a peroxisome proliferator-activated receptor-gamma activator in myocardial ischemia and reperfusion in pigs. Diabetes 52:1187-94
Lu, L; Xu, Y; Zhu, P et al. (2001) A common mechanism for concurrent changes of diastolic muscle length and systolic function in intact hearts. Am J Physiol Heart Circ Physiol 280:H1513-8

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