Cardiac dysfunction induced by high-fat diet is associated with altered myocardial insulin signalling in rats.
OBJECTIVE
Diabetic cardiomyopathy (DCM) is common in type 2 diabetes. In DCM, insulin resistance may alter cardiac substrate supply and utilisation leading to changes in myocardial metabolism and cardiac function. In rats, exposure to excessive alimentary fat, inducing a type 2 diabetic phenotype, may result in myocardial insulin resistance and cardiac functional changes resembling DCM.


METHODS
Rats received high-fat (HFD) or low-fat (LFD) diets for 7 weeks. Prior to killing, insulin or saline was injected i.p. Contractile function and insulin signalling were assessed in papillary muscles and ventricular lysates, respectively.


RESULTS
Fasting and post-load blood glucose levels were increased in HFD- vs LFD-rats (all p < 0.02). Mean heart weight, but not body weight, was increased in HFD-rats (p < 0.01). HFD-hearts showed structural changes and triglyceride accumulation. HFD-muscles developed higher baseline and maximum forces, but showed impaired recovery from higher workloads. Insulin-associated modulation of Ca2+-induced force augmentation was abolished in HFD-muscles. HFD reduced insulin-stimulated IRS1-associated phosphatidylinositol 3'-kinase activity and phosphorylation of protein kinase B, glycogen synthase kinase-3beta, endothelial nitric oxide synthase, and forkhead transcription factors by 40-60% (all p < 0.05). Insulin-mediated phosphorylation of phospholamban, a critical regulator of myocardial contractility, was decreased in HFD-hearts (p < 0.05).


CONCLUSIONS
HFD induced a hypertrophy-like cardiac phenotype, characterised by a higher basal contractile force, an impaired recovery from increased workloads and decreased insulin-mediated protection against Ca2+ overload. Cardiac dysfunction was associated with myocardial insulin resistance and phospholamban hypophosphorylation. Our data suggest that myocardial insulin resistance, resulting from exposure to excessive alimentary fat, may contribute to the pathogenesis of diabetes-related heart disease.
Ouwens
D M
DM
Department of Molecular Cell Biology, Leiden University Medical Centre, Wassenaarseweg 72, 2333 AL, Leiden, The Netherlands, d.m.ouwens@lumc.nl.
Boer
C
C
Fodor
M
M
de Galan
P
P
Heine
R J
RJ
Maassen
J A
JA
Diamant
M
M
D000818:Animals; D018752:Diet, Fat-Restricted; D004041:Dietary Fats / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D006352:Heart Ventricles; D007328:Insulin / Q000502:physiology*; D008297:Male; D023421:Models, Animal; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014280:Triglycerides / Q000378:metabolism
D004041:Dietary Fats; D007328:Insulin; D014280:Triglycerides