Cardiac dysfunction induced by high-fat diet is associated with altered myocardial insulin signalling in rats

Aims/hypothesis: 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. Materials and 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 Ca 2+-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-3β, 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