Long term liver specific glucokinase gene defect induced diabetic cardiomyopathy by up regulating NADPH oxidase and down regulating insulin receptor and p-AMPK

BACKGROUND: The liver-specific glucokinase knockout (gck(w/–)) mouse experiences long-term hyperglycemia and insulin resistance. This study was designed to evaluate the functional and structural changes in the myocardium of 60 week-old gck(w/–) mice, and to investigate the effect of rosiglitazone on the myocardium in this model. METHODS: 60 week-old gck(w/–) mice were randomly divided into 3 groups: gck(w/–), gck(w/–) mice treated with insulin (1 U/kg) and gck(w/–) mice treated with rosiglitazone (18 mg/kg). Insulin or rosiglitazone treatment was for 4 weeks. Gck(w/w) litermates were used as controls. Echocardiography, electrocardiogram, biochemical, histopathological, ultrastructural, real time PCR and Western blot studies were performed to examine for structural and functional changes. RESULTS: Long-term liver-specific gck knockout in mice elicits hyperglycaemia and insulin resistance. Compared to age matched gck(w/w) mice, 60 week-old gck(w/–) mice showed decreased LV internal dimension, increased posterior wall thickness, lengthened PR and QRS intervals, up-regulated MLC2 protein expression, decreased SOD activity, increased MDA levels and up-regulated Cyba mRNA. Morphological studies revealed that there was an increase in the amount of PAS and Masson positively stained material, as did the number and proportion of the cell occupied by mitochondria in the gck(w/–) mice. Western blot analysis revealed that the levels of the insulin receptor, Akt, phosphorylated AMPK beta and phosphorylated ACC were reduced in gck(w/–) mice. These effects were partly attenuated or ablated by treatment with rosiglitazone. CONCLUSIONS: Our results indicate that changes in the myocardium occur in the liver-specific glucokinase knockout mouse and suggest that reduced glucokinase expression in the liver may induce diabetic cardiomyopathy by up regulating NADPH oxidase and down regulating insulin receptor and p-AMPK protein levels. Rosiglitazone treatment may protect against diabetic cardiomyopathy by altering the levels of a set of proteins involved in cardiac damage.