The incidence of heart failure is up to five fold higher in diabetics compared to the general population. It has been proposed that the increased risk of heart failure is the result of the development of a primary cardiomyopathy. Previous studies by others of severe (7-10 fold increase in serum glucose) and acute (within 48 hours of treatment) diabetes have indicated that myocardial glucose transport, phosphorylation and oxidation are reduced. However, these studies did not determine whether these alterations were associated with abnormal function. The relevance of these investigations to the clinical manifestation of diabetes-associated heart failure has been questioned since the development of heart failure is a chronic rather than an acute process. Depressed cardiac function has been reported following induction of a mild diabetic state; this was only apparent after several weeks of diabetes and the metabolic changes have not been characterized in this model. The goals of this proposal are to define the metabolic alterations in the diabetic heart and to determine whether the changes in cardiac function caused by diabetes can be accounted for by changes in metabolism. Our preliminary studies show that there is a profound decrease in glucose oxidation seen one week after induction of a mild diabetic state in rats. This is due primarily to an inhibition at pyruvate dehydrogenase and can be reversed by dichloroaceate. Furthermore, we have found that after six weeks of diabetes this inhibition is more severe and irreversible. Concomitant with the greater metabolic derangements in hearts from six week diabetic animals there is also a reduction in function compared to the one week diabetic group. These results support our main hypothesis that diabetes leads to alterations in cardiac metabolism which precede and are causally related to abnormalities in cardiac function. As a consequence of our exciting preliminary data, our strategy is to correlate changes in substrate oxidation with changes in cardiac function, in hearts from normal and diabetic rats. Diabetes will be induced by treatment with streptozotocin. 13C NMR spectroscopy enables the noninvasive study of cardiac biochemistry, while simultaneously monitoring cardiac function. Thus, it is ideally suited to the study of the diabetic heart and will be used to noninvasively measure substrate utilization and metabolic fluxes in the normal and diabetic heart. The proposed experiments will focus on substrate oxidation in hearts from control and diabetic animals. We will quantify in absolute terms the flux through the TCA cycle and determine the relative contributions of different substrates to the overall flux. The effects of short and long term insulin treatment on the alterations in metabolism and function will also be investigated. The studies will be carried out on perfused hearts from normal and 1 week diabetic rats when cardiac function is normal and 6 week diabetic rats when cardiac function is compromised. These studies will provide a better understanding of the pathogenesis of heart failure in diabetes and further our knowledge of the relationship between cardiac function and metabolism.
