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Treatment of type 2 diabetic db/db mice with a novel PPAR agonist improves cardiac metabolism but not contractile function

¹Department of Pharmacology and Therapeutics and ²Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, T2N 4N1 Canada; ³Department of Medical Physiology, University of Tromsø, N-9037 Tromso, Norway; and ⁴Department of Metabolic Disorders, Merck Research Laboratories, Rahway, New Jersey 07065

Submitted 17 July 2003 ; accepted in final form 26 October 2003

Hearts from insulin-resistant type 2 diabetic db/db mice exhibit features of a diabetic cardiomyopathy with altered metabolism of exogenous substrates and reduced contractile performance. Therefore, the effect of chronic oral administration of 2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid (COOH), a novel ligand for peroxisome proliferator-activated receptor- that produces insulin sensitization, to db/db mice (30 mg/kg for 6 wk) on cardiac function was assessed. COOH treatment reduced blood glucose from 27 mM in untreated db/db mice to a normal level of 10 mM. Insulin-stimulated glucose uptake was enhanced in cardiomyocytes from COOH-treated db/db hearts. Working perfused hearts from COOH-treated db/db mice demonstrated metabolic changes with enhanced glucose oxidation and decreased palmitate oxidation. However, COOH treatment did not improve contractile performance assessed with ex vivo perfused hearts and in vivo by echocardiography. The reduced outward K⁺ currents in diabetic cardiomyocytes were still attenuated after COOH. Metabolic changes in COOH-treated db/db hearts are most likely indirect, secondary to changes in supply of exogenous substrates in vivo and insulin sensitization.

diabetic cardiomyopathy; cardiac metabolism

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