Type 1 diabetic cardiomyopathy in the Akita (Ins2) mouse model is characterized by lipotoxicity and diastolic dysfunction with preserved systolic function

Basu R, Oudit GY, Wang X, Zhang L, Ussher JR, Lopaschuk GD, Kassiri Z. Type 1 diabetic cardiomyopathy in the Akita (Ins2) mouse model is characterized by lipotoxicity and diastolic dysfunction with preserved systolic function. Am J Physiol Heart Circ Physiol 297: H2096 –H2108, 2009. First published October 2, 2009; doi:10.1152/ajpheart.00452.2009.—Diabetic cardiomyopathy is an important contributor to diastolic and systolic heart failure. We examined the nature and mechanism of the cardiomyopathy in Akita (Ins2) mice, a model of genetic nonobese type 1 diabetes that recapitulates human type 1 diabetes. Cardiac function was evaluated in male Ins2 and their littermate control (Ins2) mice using echocardiography and tissue Doppler imaging, in vivo hemodynamic measurements, as well as ex vivo working heart preparation. At 3 and 6 mo of age, Ins2 mice exhibited preserved cardiac systolic function compared with Ins2 mice, as evaluated by ejection fraction, fractional shortening, left ventricular (LV) end-systolic pressure and maximum rate of increase in LV pressure in vivo, cardiac work, cardiac power, and rate-pressure product ex vivo. Despite the unaltered systolic function, Ins2 mice exhibited significant and progressive diastolic dysfunction at 3 and 6 mo of age compared with Ins2 mice as assessed by tissue and pulse Doppler imaging (E-wave velocity, isovolumetric relaxation time) and by in vivo hemodynamic measurements (LV end-diastolic pressure, time constant of LV relaxation, and maximum rate of decrease in LV pressure). We found no evidence of myocardial hypertrophy or fibrosis in the Ins2 myocardium. Consistent with the lack of fibrosis, expression of procollagentype I, procollagentype III, and fibronectin were not increased in these hearts. Ins2 hearts showed significantly reduced sarcoplasmic reticulum Ca -ATPase 2a (cardiac sarcoplasmic reticulum Ca pump) levels, elevated -myosin heavy chain isoform, increased long-chain fatty acids, and triacylglycerol with evidence of lipotoxicity, as indicated by a significant rise in ceramide, diacylglycerol, and lipid deposits in the myocardium. Consistent with metabolic perturbation, and a switch to fatty acid oxidation from glucose oxidation in Ins2 hearts, expression of mitochondrial long-chain acyl-CoA dehydrogenase and pyruvate dehydrogenase kinase isoform 4 were increased. Insulin treatment reversed the diastolic dysfunction, the elevated B-type natriuretic peptide and -myosin heavy chain, and the reduced sarcoplasmic reticulum Ca -ATPase 2a levels with abolition of cardiac lipotoxicity. We conclude that early type 1 diabetic cardiomyopathy is characterized by diastolic dysfunction associated with lipotoxic cardiomyopathy with preserved systolic function in the absence of interstitial fibrosis and hypertrophy.