Cardiac function and metabolism in Type 2 diabetic mice after treatment with BM 17.0744, a novel PPAR-α activator

Abstract

Hearts from diabetic db/ db mice, a model of Type 2 diabetes, exhibit left ventricular failure and altered metabolism of exogenous substrates. Peroxisome proliferator-activated receptor-α (PPAR-α) ligands reduce plasma lipid and glucose concentrations and improve insulin sensitivity in db/ db mice. Consequently, the effect of 4- to 5-wk treatment of db/ db mice with a novel PPAR-α ligand (BM 17.0744; 25–38 mg · kg−1· day−1), commencing at 8 wk of age, on ex vivo cardiac function and metabolism was determined. Elevated plasma concentrations of glucose, fatty acids, and triacylglycerol (34.0 ± 3.6, 2.0 ± 0.4, and 0.9 ± 0.1 mM, respectively) were reduced to normal after treatment with BM 17.0744 (10.8 ± 0.6, 1.1 ± 0.1, and 0.6 ± 0.1 mM). Plasma insulin was also reduced significantly in treated compared with untreated db/ db mice. Chronic treatment of db/ db mice with the PPAR-α agonist resulted in a 50% reduction in rates of fatty acid oxidation, with a concomitant increase in glycolysis (1.7-fold) and glucose oxidation (2.3- fold). Correction of the diabetes-induced abnormalities in systemic and cardiac metabolism after BM 17.0744 treatment did not, however, improve left ventricular contractile function.