Role and mechanism of cardiac insulin resistance in occurrence of heart failure caused by myocardial hypertrophy.

Cardiac insulin resistance plays an important role in the development of heart failure, but the underlying mechanisms remain unclear. Here, we found that hypertrophic hearts exhibit normal cardiac glucose oxidation rates, but reduced fatty acid oxidation rates, compared to Sham controls under basal (no insulin) conditions. Furthermore, insulin stimulation attenuated insulin's effects on cardiac substrate utilization, suggesting the development of cardiac insulin resistance. Consistent with insulin resistance, p38-MAPK protein levels were reduced in hypertrophic hearts. By contrast, systemic hyperinsulin-euglycemic clamp indicated normal insulin sensitivity. Finally, electron microscopy revealed severe mitochondrial damage in the hypertrophic myocardium. Our results indicate that that cardiac insulin resistance caused by cardiac hypertrophy is associated with mitochondrial damage and cardiac dysfunction. Moreover, our findings suggest that cardiac insulin resistance is independent of systemic insulin resistance, which is also a risk factor for heart failure.