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

Contractile function and substrate metabolism were characterized in perfuse d hearts from genetically diabetic C57BL/KsJ-lepr(db)/lepr(db) (db/db) mice and their non-diabetic lean littermates. Contractility was assessed in wor king hearts by measuring left ventricular pressures and cardiac power. Rate s of glycolysis, glucose oxidation, and fatty acid oxidation were measured using radiolabeled substrates ([5-H-3]glucose, [U-C-14]glucose, and [9,10-H -3]palmitate) in the perfusate. Contractile dysfunction in db/db hearts was evident, with increased left ventricular end diastolic pressure and decrea sed left ventricular developed pressure, cardiac output, and cardiac power. The rate of glycolysis from exogenous glucose in diabetic hearts was 48% o f 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-indu ced contractile dysfunction was tested using perfused hearts from transgeni c db/db mice that overexpress GLUT-4 glucose transporters. Both glucose met abolism and palmitate metabolism were normalized in hearts from db/db-human insulin-regulatable glucose transporter (hGLUT-4) hearts, as was contracti le function. These findings strongly support a causative role of impaired m etabolism in the cardiomyopathy observed in db/db diabetic hearts.