Involvement of Insulin Resistance in the Protective Effect of Metformin Against Alcoholic Liver Injury

Background Alcoholic liver disease (ALD) continues to be a major cause of morbidity worldwide. The exact mechanisms for ALD pathogenesis are not fully understood. There is currently no known available drug for ALD. Previous studies have suggested that ethanol (EtOH)-induced hepatic insulin resistance, through the inhibition of adenosine monophosphate-activated protein kinase (AMPK) and the expression of adiponectin as well as downstream enzymes, contribute to the development of ALD. This study was to determine the effects of EtOH on AMPK activity as well as the protective effect of metformin. Methods Forty male Wistar rats weighing 200 +/- 20g were randomized into 4 groups (n=10) as follows: A=control grouprats received rodent chow; B=control+metformin grouprats received metformin (200mg/kg/d intragastrically [IG]) at 21:00; C=EtOH grouprats were gavaged with alcohol of gradually increasing concentrations (30to 60%, 5to 9g/kg/d) twice a day (9:00 and 16:00); D=EtOH+metformin grouprats received the same amount of EtOH as the rats in group C, and in addition received metformin (200mg/kg/d IG) at 21:00. After 16weeks, blood and liver samples were collected for further study. Results Chronic EtOH consumption led to liver injury both histologically and biochemically accompanied by insulin resistance, reduced AMPK activity, and dysregulation of downstream enzymes. Decreased levels of circulating adiponectin and decreased expression of proliferator-activated receptor gamma coactivator-1 (PGC-1) and peroxisome proliferator-activated receptors- (PPAR-) in the hepatic tissue were observed. Treatment with metformin attenuated the severity of liver injury, restored AMPK activity and normalized the expression of acetyl-CoA carboxylase and fatty acid synthase. In addition, metformin also increased the circulating adiponectin and liver adiponectin receptor 2 expression. Furthermore, PGC-1 and PPAR- activities were also restored. Conclusions EtOH exposure induces hepatic insulin resistance. Metformin improved insulin resistance and reversed liver injury through the activation of AMPK and normalized adiponectin signaling making metformin a promising drug for the treatment of ALD.