Strategies for preventing and curing insulin resistance in lipid-overloaded cardiac myocytes

Insulin resistance is a central pathological mechanism of type 2 diabetes mellitus. Diabetic cardiomyopathy and heart failure are frequent co-morbid conditions in type 2 diabetic patients. Long-chain fatty acids (LCFAs) are the major energy source for the heart to sustain contractile activity, and the diabetic heart becomes almost entirely dependent on LCFAs for energy production. Elevated intracellular levels and prolonged accumulation of LCFA metabolites worsen the state of insulin resistance, and further induce diabetic cardiomyopathy and heart failure. It is indicated that sarcolemmal fatty acid uptake and mitochondrial β-oxidation are the rate-limiting steps in cardiac LCFA flux and utilization. Therefore, the inhibitions of carnitine palmitoyltransferase (CPT-I), β-oxidation enzymes and CD36/plasma membrane fatty acid-binding protein (FABPpm) translocation are the preferable strategies of limiting LCFA entry and LCFA metabolite accumulation, thus regressing cardiac insulin resistance, and eventually preventing diabetic heart failure.