Abstract P243: Simultaneous Decrease in Glucose Uptake, Increase in Glucose Oxidation, and Improved Contractile Function by Hearts from Sucrose-Fed Rats

Abstract

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”). 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 of sucrose-fed animals 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 H 2 O; 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 (PDH) activity, and lower uncoupling protein 3 (UCP3) expression. In conclusion, insulin resistance promotes adaptation of the stressed heart by increasing glucose oxidation while limiting excess fuel uptake. Our findings call for a new interpretation of the glucose-fatty acid cycle in the heart.