It is well established that insulin-dependent diabetes in man and animals alters myocardial energy metabolism. These metabolic disturbances are believed to be major factors contributing to the decline in myocardial contractility that occurs in the diabetic heart. The actual mechanism(s) responsible for these metabolic and functional deficits, however, are unclear. The hypothesis of this proposal is that exercise-conditioning will prevent or limit the progressive functional decline of hearts from diabetic animals by effecting specific metabolic adaptations that preserve the functional status of the myocardium. By identifying the beneficial metabolic adaptations that occur in exercised diabetic animals, it will be possible to identify the critical metabolic changes that occur in the diabetic heart which lead to the progressive contractile dysfunction of the myocardium. The results obtained from the proposed studies will also be analyzed to evaluate the potential advisability of exercise-training for diabetic patients. Four groups of rats will be studied: sedentary control, trained control, sedentary diabetic and trained diabetic. Diabetes will be induced by i.v. administration of streptozotocin (50 mg/kg). Rats will be trained on a treadmill for 8 wk. The effects of diabetes and exercise training on cardiac contractility will be studied by measuring in vivo cardiac contractility, and by constructing Frank-Starling curves from isolated perfused working hearts. The vulnerability of the isolated perfused heart to global ischemia will also be assessed. Hearts will be perfused with concentrations of glucose and free fatty acids which characterize the in vivo state. Dynamic changes in high energy phosphate metabolites will be measured using P31-nuclear magnetic resonance spectroscopy. Changes in these metabolites will be correlated to both fatty acid and glucose utilization and tissue concentrations of long-chain acyl carnitine and coenzyme A esters. Preliminary data demonstrated that diabetes results in depressed cardiac function and decreased recovery of cardiac output after ischemia and reperfusion, relative to control hearts. Exercise training of control rats was shown to increase cardiac performance. Hearts from exercise trained rats had elevated cardiac carnitine levels, while diabetic hearts were deficient in carnitine. Carnitine therapy to diabetic rats was shown to prevent the carnitine deficiency and improve the recovery of cardiac output after ischemia and reperfusion. Although the metabolic factors that contribute to the functional disturbances which develop in the diabetic heart have not been elucidated unequivocally, abnormal carnitine metabolism and aberrant substrate utilization implicated as probably sites of action.
