Altered metabolism causes cardiac dysfunction in perfused hearts from diabetic (db/db) mice

1 Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada T2N 4N1; 2 Institute of Medical Biology, University of Tromsø, N-9037 Tromsø, Norway; and 3 Department of Metabolic Diseases, Central Research Division, Pfizer, Groton, Connecticut 06340 Contractile function and substrate metabolism were characterized in perfused hearts from genetically diabetic C57BL/KsJ- lepr db / lepr db ( db/db ) mice and their non-diabetic lean littermates. Contractility was assessed in working hearts by measuring left ventricular pressures and cardiac power. Rates of glycolysis, glucose oxidation, and fatty acid oxidation were measured using radiolabeled substrates ([5- 3 H]glucose, [U- 14 C]glucose, and [9,10- 3 H]palmitate) in the perfusate. Contractile dysfunction in db/db hearts was evident, with increased left ventricular end diastolic pressure and decreased left ventricular developed pressure, cardiac output, and cardiac power. The rate of glycolysis from exogenous glucose in diabetic hearts was 48% of control, whereas glucose oxidation was depressed to only 16% of control. In contrast, palmitate oxidation was increased twofold in db/db hearts. The hypothesis that altered metabolism plays a causative role in diabetes-induced contractile dysfunction was tested using perfused hearts from transgenic db/db mice that overexpress GLUT-4 glucose transporters. Both glucose metabolism and palmitate metabolism were normalized in hearts from db/db -human insulin-regulatable glucose transporter (hGLUT-4) hearts, as was contractile function. These findings strongly support a causative role of impaired metabolism in the cardiomyopathy observed in db/db diabetic hearts. diabetic cardiomyopathy