Mitochondria respiration and susceptibility to ischemia–reperfusion injury in diabetic hearts

Abstract

Cardiovascular complications are the primary cause of death for diabetic patients. Clinical and experimental observation has showed the development of dysfunctional cardiomyopathy as one of the main complications of diabetes. Whether the cardiomyopathy results from an increased susceptibility of cardiac tissue to ischemic insult or from a specific functional defect of cardiac mitochondria is a controversial issue. The investigation of possible functional defect in cardiac mitochondria from diabetic rats indicates a decline in state 3 respiration only in animals presenting a marked decrease in body weight. Mitochondria from rats presenting a level of hyperglycemia similar to diabetic animals but not the marked weight loss typical of the latter group show no decline in state 3 respiration, the values being indistinguishable from those of control mitochondria. Mitochondria from hyperglycemic rats, however, show a 15–20% increase in state 4 oxygen consumption but only when glutamate is used as energetic substrate, as compared to a 40–50% increase in state 4 respiration in mitochondria from diabetic rats under similar experimental conditions. This phenomenon is unrelated to diabetes duration, as it is observed at 2 as well as 8 weeks after diabetes onset. Taken together, these data argue against hyperglycemia per se being a direct cause of the decline in state 3 oxygen consumption observed in cardiac mitochondria of type-I diabetic rats and indicate that differences exist in cardiac mitochondrial function in rats generically labeled as diabetic. These differences can contribute to explain discrepancies in experimental results reported by various groups in the field and provide an additional parameter to be taken into consideration in evaluating the varying sensitivity of diabetic hearts to ischemia–reperfusion injury.