Metallothionein alleviates cardiac contractile dysfunction induced by insulin resistance:: role of Akt phosphorylation, PTB1B, PPARγ and c-Jun

Aims/hypothesis: Insulin resistance is concomitant with metabolic syndrome, oxidative stress and cardiac contractile dysfunction. However, the causal relationship between oxidative stress and cardiac dysfunction is unknown. This study was designed to determine the impact of overexpression of the cardiac antioxidant metallothionein on cardiac dysfunction induced by insulin resistance in mice. Methods: Whole-body insulin resistance was generated in wild-type FVB and metallothionein transgenic mice by feeding them with sucrose for 12 weeks. Contractile and intracellular Ca-90(90)90(2+ properties were evaluated in ventricular myocytes using an IonOptix system. The contractile indices analysed included: peak shortening (PS), time to 90% PS (TPS)), time to 90% relengthening (TR(), half-width duration, maximal velocity of shortening (+dL/dt) and relengthening (-dL/dt), fura-fluorescence intensity change (DFFI) and decay rate (t). Results: The sucrose-fed mice displayed glucose intolerance, enhanced oxidative stress, hyperinsulinaemia, hypertriglyceridaemia and normal body weight. Compared with myocytes in starch-fed mice, those from sucrose-fed mice exhibited depressed PS, +dL/dt, -dL/dt, prolonged TR) (and decay rate, and reduced DFFI associated with normal TPS)(90) and half-width duration. Western blot analysis revealed enhanced basal, but blunted insulin (15 mU/g)-stimulated Akt phosphorylation. It also showed elevated expression of insulin receptor b, insulin receptor tyrosine phosphorylation, peroxisome proliferator-activated receptor g, protein tyrosine phosphatase 1B and phosphorylation of the transcription factor c-Jun, associated with a reduced fold increase of insulin-stimulated insulin receptor tyrosine phosphorylation in sucrose-fed mice. All western blot findings may be attenuated or ablated by metallothionein. Conclusions/interpretation: These data indicate that oxidative stress may play an important role in cardiac contractile dysfunction associated with glucose intolerance and possibly related to alteration in insulin signalling at the receptor and post-receptor levels.