REDUCING DIABETIC CARDIOMYOPATHY: INCREASING GLYCOLYSIS

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Applicant's Abstract It is well established that diabetes reduces cardiac glycolysis. Further, it is known that impaired glycolysis predisposes to ischemic damage, cardiomyopathy and contractile deficits. Each of these cardiac problems is characteristic of diabetic cardiomyopathy. Together, these findings suggest that decreased glycolysis has an important role in diabetic cardiomyopathy. However, diabetes is a complex disease with many deficits in the heart and throughout the body. This proposal focuses on the hypothesis that there is a causal relationship between decreased glycolysis and diabetic cardiomyopathy. To test this proposal, the applicants will produce four separate transgenic models that express genes to increase glycolysis, specifically in the heart. Transgenes for the GLUT 4 glucose transporter, yeast hexokinase, bisphosphatase deficient 2,6 phosphofructo-kinase/fructose-2,6 bisphosphatase and glyceraldehyde 3-phosphate dehydrogenase will be overexpressed. Each of these genes controls an activity that is reduced in the diabetic heart and controls glycolysis under aerobic or ischemic conditions. The applicants have already developed the yeast hexokinase model and demonstrated increased cardiac glycolysis. Transgenic mice with increased glycolysis will be crossed to a transgenic model of severe, prolonged and early onset diabetes, which they have found to display morphological and functional features of diabetic cardiomyopathy. Diabetic mice carrying the glycolytic transgenes will be compared for signs of cardiomyopathy to diabetic mice without glycolytic transgenes. Hearts will be analyzed for differences in morphology, contractility, sensitivity to ischemia and mitochondrial damage. These studies will provide a definitive test of the role of impaired glycolysis in diabetic cardiomyopathy and sensitization to ischemia.