Abstract 12051: Myocardial Insulin Resistance Preserves Metabolic Responsiveness in the Stressed Rat Heart
The heart responds to acute hemodynamic stress by increasing carbohydrate oxidation. This metabolic response is impaired in diabetes when excess fatty acid availability inhibits glucose oxidation (Randle's “glucose-fatty acid cycle”). The impaired glucose uptake and oxidation are believed to result in energy deficiency and poor contractile function. We now propose that in the heart insulin resistance, defined by impaired uptake of glucose in response to insulin, is an endogenous protective mechanism which prevents excess uptake of fuel when supply is increased. To test this we fed Sprague-Dawley rats either a high-sucrose diet or regular chow diet. After 5 to 8 weeks systemic insulin sensitivity was impaired in sucrose-fed rats. Hearts were then perfused ex vivo in the working mode to measure function and metabolism. Rates of glucose uptake by the heart were decreased in response to insulin. Cardiac power remained unchanged in hearts perfused with either normal (5mM glucose; 0.4mM oleate; 0.5ng/ml insulin) or high (25mM glucose; 0.8mM oleate; 5ng/ml insulin) concentrations of substrates. However, cardiac power increased for the insulin-resistant hearts compared to controls when a hemodynamic stress (afterload raised from 100 to 140cm H2O; 1µM epinephrine) was superimposed on nutrient stress. The ratio of glucose-to-oleate oxidation was also markedly increased in these hearts, as was cardiac efficiency. Higher glucose oxidation rates correlated with increased pyruvate dehydrogenase activity. Tissue levels of intermediate metabolites of the glycolytic pathway (glucose 6-phosphate) and of the fatty acid utilization pathway (Oleoyl-CoA) were significantly reduced. The mRNA expression levels of genes encoding for enzymes involved in substrate selection in the heart showed minor changes or no differences. However, uncoupling protein 3 levels were reduced by 40% in the heart of sucrose-fed rats. In conclusion, myocardial insulin resistance promotes adaptation of the stressed heart by increasing glucose oxidation while limiting excess fuel uptake. The uncoupling protein 3 may play a role in myocardial substrate partitioning. Our findings call for a new interpretation of the glucose-fatty acid cycle in the heart.
- © 2011 by American Heart Association, Inc.