Metabolic energy metabolism in diabetes: therapeutic implications.

Diabetic alterations of myocardial metabolism result mainly from malfunctions of acetyl-coenzyme A carboxylase, carnitine-palmitoyl-transferase-I and pyruvate-dehydrogenase inducing an overshoot of fatty acid oxidation that inhibits glucose oxidation. Gene expression of pyruvate-dehydrogenase and glucose transporters and depression of the third step of the mitochondrial respiratory chain also contribute to the diabetic alterations of myocardial metabolism. Ischaemic cardiovascular alterations are common and treatment is rarely successful in cases of diabetes since fatty acid oxidation is the costliest metabolic pathway for oxygen. Thus, in diabetes, aerobic glycolysis gradually shifts to anaerobic glycolysis under ischaemia, with accumulation of lactate and acid metabolites that in turn induce myocardial deterioration, Animal experiments have demonstrated that elective depression of activity of carnitine-palmitoyl-transferase-I enzyme-activity promotes glucose oxidation and early rapid recovery of myocardial contractility, especially under diabetic conditions. To reduce diabetic alterations of myocardial metabolism, anti-diabetic treatment must be switched to insulin during the acute ischaemic and post-ischaemic period of coronary diseases. Trimetazidine optimizes energy metabolism by selectively inhibiting action of the 3-ketoacyl-coenzyme A thiolase enzyme involved in beta-oxidation and inhibiting the overshoot of fatty oxidation. Trimetazidine, as the first 3-ketoacyl-coenzyme A thiolase inhibitor, therefore provides permanent myocardial cytoprotection in stable angina pectoris. However, in our experience, this beneficial anti-anginal effect is only observed in well-controlled situations.