Insulin resistance improves metabolic and contractile efficiency in stressed rat heart

Insulin resistance is a prominent feature in heart failure, while hyperglycemia impairs cardiac contraction. We propose that decreased insulin-mediated glucose uptake by the heart preserves cardiac function in response to metabolic and hemodynamic stress. To test this hypothesis, we fed rats a high-sucrose diet (HSD). Energy substrate metabolism and cardiac work were determined ex vivo in a sequential protocol simulating metabolic and hemodynamic stress. Compared to chow-fed, control rats, HSD impaired myocardial insulin responsiveness and induced profound metabolic changes in the heart, characterized by reduced rates of glucose uptake (7.91 +/- 0.30 vs. 10.73 +/- 0.67 mu mol/min/g dry weight; P<0.001) but increased rates of glucose oxidation (2.38 +/- 0.17 vs. 1.50 +/- 0.15 mu mol/min/g dry weight; P<0.001) and oleate oxidation (2.29 +/- 0.11 vs. 1.96 +/- 0.12 mu mol/min/g dry weight; P<0.05). Tight coupling of glucose uptake and oxidation and improved cardiac efficiency were associated with a reduction in glucose 6-phosphate and oleoyl-CoA levels, as well as a reduction in the content of uncoupling protein 3. Our results suggest that insulin resistance lessens fuel toxicity in the stressed heart. This calls for a new exploration of the mechanisms regulating substrate uptake and oxidation in the insulin-resistant heart.-Harmancey, R., Lam, T. N., Lubrano, G. M., Guthrie, P. H., Vela, D., Taegtmeyer, H. Insulin resistance improves metabolic and contractile efficiency in stressed rat heart. FASEB J. 26, 3118-3126 (2012). www.fasebj.org