Type 1 diabetic cardiomyopathy in the Akita (Ins2WT/C96Y) mouse model is characterized by lipotoxicity and diastolic dysfunction with preserved systolic function

Am J Physiol Heart Circ Physiol. 2009 Dec;297(6):H2096-108. doi: 10.1152/ajpheart.00452.2009. Epub 2009 Oct 2.

Abstract

Diabetic cardiomyopathy is an important contributor to diastolic and systolic heart failure. We examined the nature and mechanism of the cardiomyopathy in Akita (Ins2(WT/C96Y)) mice, a model of genetic nonobese type 1 diabetes that recapitulates human type 1 diabetes. Cardiac function was evaluated in male Ins2WT/C96Y and their littermate control (Ins2WT/WT) 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, Ins2WT/C96Y mice exhibited preserved cardiac systolic function compared with Ins2WT/WT 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, Ins2WT/C96Y mice exhibited significant and progressive diastolic dysfunction at 3 and 6 mo of age compared with Ins2WT/WT 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 Ins2WT/C96Y myocardium. Consistent with the lack of fibrosis, expression of procollagen-alpha type I, procollagen-alpha type III, and fibronectin were not increased in these hearts. Ins2WT/C96Y hearts showed significantly reduced sarcoplasmic reticulum Ca2+-ATPase 2a (cardiac sarcoplasmic reticulum Ca2+ pump) levels, elevated beta-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 Ins2WT/C96Y 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 beta-myosin heavy chain, and the reduced sarcoplasmic reticulum Ca2+-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl-CoA Dehydrogenase, Long-Chain / metabolism
  • Age Factors
  • Animals
  • Blood Glucose / metabolism
  • Cardiomyopathies / diagnostic imaging
  • Cardiomyopathies / drug therapy
  • Cardiomyopathies / genetics*
  • Cardiomyopathies / metabolism
  • Cardiomyopathies / physiopathology
  • Ceramides / metabolism
  • Diabetes Mellitus, Type 1 / complications
  • Diabetes Mellitus, Type 1 / diagnostic imaging
  • Diabetes Mellitus, Type 1 / drug therapy
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 1 / physiopathology
  • Diastole
  • Diglycerides / metabolism
  • Disease Models, Animal
  • Disease Progression
  • Echocardiography, Doppler, Pulsed
  • Fatty Acids / metabolism
  • Hypoglycemic Agents / pharmacology
  • Insulin / blood
  • Insulin / genetics*
  • Insulin / pharmacology
  • Lipid Metabolism / drug effects
  • Lipid Metabolism / genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mitochondria, Heart / metabolism
  • Myocardial Contraction* / drug effects
  • Myocardium / metabolism*
  • Myosin Heavy Chains / metabolism
  • Natriuretic Peptide, Brain / metabolism
  • Protein Serine-Threonine Kinases / metabolism
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
  • Stroke Volume
  • Systole
  • Triglycerides / metabolism
  • Ventricular Dysfunction, Left / diagnostic imaging
  • Ventricular Dysfunction, Left / drug therapy
  • Ventricular Dysfunction, Left / genetics*
  • Ventricular Dysfunction, Left / metabolism
  • Ventricular Dysfunction, Left / physiopathology
  • Ventricular Pressure

Substances

  • Atp2a2 protein, rat
  • Blood Glucose
  • Ceramides
  • Diglycerides
  • Fatty Acids
  • Hypoglycemic Agents
  • Insulin
  • MYH7 protein, rat
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Triglycerides
  • Natriuretic Peptide, Brain
  • Acyl-CoA Dehydrogenase, Long-Chain
  • Protein Serine-Threonine Kinases
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Myosin Heavy Chains