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

Abstract

BackgroundThe liver-specific glucokinase knockout (gckw/–) 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 gckw/– mice, and to investigate the effect of rosiglitazone on the myocardium in this model.Methods60 week-old gckw/– mice were randomly divided into 3 groups: gckw/–, gckw/– mice treated with insulin (1 U/kg) and gckw/– mice treated with rosiglitazone (18 mg/kg). Insulin or rosiglitazone treatment was for 4 weeks. Gckw/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.ResultsLong-term liver-specific gck knockout in mice elicits hyperglycaemia and insulin resistance. Compared to age matched gckw/w mice, 60 week-old gckw/– 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 gckw/– mice. Western blot analysis revealed that the levels of the insulin receptor, Akt, phosphorylated AMPK beta and phosphorylated ACC were reduced in gckw/– mice. These effects were partly attenuated or ablated by treatment with rosiglitazone.ConclusionsOur 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.

Efficacy of Berberine in Patients with Non-Alcoholic Fatty Liver Disease

“…GCK was for regulation of glucose metabolism rate[ 31 ], and also increased after BBR treatment. It has been reported that BBR could decrease insulin resistance by activating liver AMPK [ 32 ], and hepatic GCK up-regulation might relate to the activation of hepatic AMPK pathway[ 33 ]. Therefore, BBR may have multiple effects on liver genes associated with lipid or glucose metabolism.…”

Updating Experimental Models of Diabetic Cardiomyopathy

“…Specific target genes have been modulated to create DCM-like models in rodents ( Table 2 ). As detected in T1DM patients, cardiac dysfunction, hypertrophy, and fibrosis were demonstrated by upregulation of PKC β [ 96 ] or by downregulation of GLUT4 [ 97 – 99 ], phosphoinositide dependent kinase-1 (PDK1) [ 100 ], phosphoinositide-3 kinase (PI3K) [ 101 ], or glucokinase (GCK) [ 102 ] genes ( Table 2 ). Apoptosis and inflammation were less common (only in PKC β and/or PI3K), and some metabolic controversies were described.…”

Association of prediabetes-associated single nucleotide polymorphisms with microalbuminuria

“…Furthermore, Li et al demonstrated that downregulation of GCK can contribute to the development of diabetic cardiomyopathy via increased oxidative stress and insulin resistance in an experimental animal model. Lastly, Szopa et al reported that flow-mediated vasodilatation of the brachial artery is decreased in GCK mutation carriers [ 37 , 38 ]. Such findings suggest that genetic variation in the GCK gene may exert positive or negative effect(s) not only on glucose metabolism in the liver and pancreas but also on the cardiovascular protective mechanism.…”