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Open Access Original investigation

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

Hui Li1, Xi Wang1, Yiqing Mao1, Ruobi Hu1, Wei Xu1, Zhen Lei4, Na Zhou1, Ling Jin1, Tingting Guo1, Zhixin Li5, David M Irwin3, Gang Niu2* and Huanran Tan1*

Author Affiliations

1 Department of Pharmacology, Health Science Center, Peking University, 38 Xue Yuan Road, Beijing 100191, China

2 Beijing N&N Genetech Company, Beijing, China

3 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada

4 Department of Pharmacology, Ningxia Medical University, Yinchuan 750004, China

5 Department of the Integration of Chinese and Western Medicine, Health Science Center, Peking University, Beijing 100191, China

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Cardiovascular Diabetology 2014, 13:24  doi:10.1186/1475-2840-13-24

Published: 22 January 2014

Abstract

Background

The 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.

Methods

60 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.

Results

Long-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.

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.

Keywords:
Liver-specific glucokinase knockout; Diabetic cardiomyopathy; Rosiglitazone; Insulin receptor; AMPK