Shift in metabolic substrate uptake by the heart during development of alloxan-induced diabetes

Abstract

Inhibition of endothelial nitric oxide (NO) synthase (eNOS) is associated with an increase in glucose uptake by the heart. We have already shown that Type I diabetes also causes a decrease in eNOS protein expression and altered NO control of both coronary vascular resistance and oxygen consumption. Therefore, we predict that the increase in plasma glucose and the reduction in eNOS during diabetes together would result in a large increase in cardiac glucose uptake. Arterial (A) and coronary sinus (C) plasma levels of glucose, free fatty acid (FFA), β-hydroxybutyric acid (β-HBA), and lactate were measured, and myocardial uptake was calculated before and at week 1, 2, 3, and 4 of alloxan-induced diabetes. The heart of healthy dogs consumed FFA (19.2 ± 2.6 μeq/min) and lactate (19.7 ± 3.4 μmol/min). Dogs in the late stage of diabetes (at week 4) had elevated arterial β-HBA concentrations (1.6 ± 0.7 μmol/l) that were accompanied by an increased β-HBA uptake (0.3 ± 0.2 μmol/min). In contrast, myocardial lactate (–4.8 ± 3.0 μmol/min) and FFA uptake (2.5 ± 1.9 μeq/min) were significantly reduced in diabetic animals. Despite a marked hyperglycemia (449 ± 25 mg/dl), the heart did not take up glucose (–7.9 ± 4.1 mg/dl). Our results indicate significant changes in the myocardial substrate utilization in dogs only in the late stage of diabetes, at a time when myocardial NO production is already decreased.