description): Diabetes is associated with increased incidence of vascular disease and hypertension; however, there is evidence of a diabetic cardiomyopathy independent of other risk factors for heart disease. Despite the fact that approximately 90% of diabetic patients have Type 2 diabetes, the majority of the experimental studies on the effects of diabetes on the myocardium use acute models of uncontrolled Type 1 diabetes. Therefore, the goal of this project is to determine the consequences of Type 2 diabetes on cardiac metabolism and function. The investigators have shown that contractile dysfunction following diabetes can be attributed, in part, to alterations in energy metabolism. Preliminary studies also demonstrate that metabolic abnormalities are associated with the transition from insulin resistance to Type 2 diabetes and precede the development of overt contractile dysfunction. In light of these results, the hypothesis to be tested is that the development of Type 2 diabetes is associated with impaired energy production as a result of a decrease in both carbohydrate and fatty acid entry into the mitochondria. The investigators propose that these alterations in energy metabolism contribute to the development of impaired contractile function and increased susceptibility to ischemic injury. To test this hypothesis, experiments will be carried out on isolated perfused hearts form Zucker rats (ZF, fa/fa); lean non-diabetic litter mates (fa/?) and obese, non-diabetic Zucker rats (ZF, fa/fa) will be used as controls. The effects of the development of Type 2 diabetes, on myocardial substrate utilization, contractile function and the regulation of coronary flow will be investigated. They will determine whether treatment with anti-hyperglycemic agents prevent the myocardial changes associated with the development of Type 2 diabetes in the ZDF rat. 13C-NMR spectroscopic techniques will be used to quantify fluxes through metabolic pathways critical to the regulation of energy metabolism under normal conditions and following ischemia and reperfusion derangement of the myocardium that occur as a result of obesity, insulin resistance as well as Type 2 diabetes.
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