Impaired Cardiac Efficiency and Increased Fatty Acid Oxidation in Insulin-Resistant ob/ob Mouse Hearts

Abstract

Diabetes alters cardiac substrate metabolism. The cardiac phenotype in insulin-resistant states has not been comprehensively characterized. The goal of these studies was to determine whether the hearts of leptindeficient 8-week-old ob/ob mice were able to modulate cardiac substrate utilization in response to insulin or to changes in fatty acid delivery. Ob/ob mice were insulin resistant and glucose intolerant. Insulin signal transduction and insulin-stimulated glucose uptake were markedly impaired in ob/ob cardiomyocytes. Insulinstimulated rates of glycolysis and glucose oxidation were 1.5-and 1.8-fold higher in wild-type hearts, respectively, versus ob/ob, and glucose metabolism in ob/ob hearts was unresponsive to insulin. Increasing concentrations of palmitate from 0.4 mmol/l (low) to 1.2 mmol/l (high) led to a decline in glucose oxidation in wild-type hearts, whereas glucose oxidation remained depressed and did not change in ob/ob mouse hearts. In contrast, fatty acid utilization in ob/ob hearts was 1.5-to 2-fold greater in the absence or presence of 1 nmol/l insulin and rose with increasing palmitate concentrations. Moreover, the ability of insulin to reduce palmitate oxidation rates was blunted in the hearts of ob/ob mice. Under low-palmitate and insulin-free conditions, cardiac performance was significantly greater in wildtype hearts. However, in the presence of high palmitate and 1 nmol/l insulin, cardiac performance in ob/ob mouse hearts was relatively preserved, whereas function in wild-type mouse hearts declined substantially. Under all perfusion conditions, myocardial oxygen consumption was higher in ob/ob hearts, ranging from 30% higher in low-palmitate conditions to greater than twofold higher under high-palmitate conditions. These data indicate that although the hearts of glucose-intolerant ob/ob mice are capable of maintaining their function under conditions of increased fatty acid supply and hyperinsulinemia, they are insulin-resistant, metabolically inefficient, and unable to modulate substrate utilization in response to changes in insulin and fatty acid supply. Diabetes 53: 2366 -2374, 2004 D iabetes is associated with a switch in myocardial substrate utilization that results in increased fatty acid utilization and decreased glucose utilization (1,2). Most studies of myocardial energy metabolism in diabetes have been performed in models of insulin deficiency. Fewer studies in insulin-resistant animals with type 2 diabetes have also revealed that glucose and/or lactate oxidation rates are decreased and that palmitate oxidation rates are increased (3-5). Moreover, this metabolic profile is associated with reduced myocardial function. Most studies in insulinresistant mouse models have been performed at fatty acid concentrations that are similar to those seen in lean controls. Furthermore, some studies have been performed in the presence of added insulin, whereas others have been performed in the absence of insulin. Thus, it is possible that the experimental conditions might not reflect insulin ...

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