title: Involvement of insulin resistance in the protective effect of metformin against alcoholic liver injury.
abstract: 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 ± 20 g were randomized into 4 groups (n = 10) as follows: A = control group-rats received rodent chow; B = control + metformin group-rats received metformin (200 mg/kg/d intragastrically [IG]) at 21:00; C = EtOH group-rats were gavaged with alcohol of gradually increasing concentrations (30 to 60%, 5 to 9 g/kg/d) twice a day (9:00 and 16:00); D = EtOH + metformin group-rats received the same amount of EtOH as the rats in group C, and in addition received metformin (200 mg/kg/d IG) at 21:00. After 16 weeks, 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-1α (PGC-1α) and peroxisome proliferator-activated receptors-α (PPAR-α) 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-1α and PPAR-α 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.
authors.affiliation: Department of Infectious disease , Third Hospital, Hebei Medical University, Shijiazhuang, China.
authors.forename: ZhanTao
authors.initials: Z
authors.lastname: Zhu
authors.forename: ZhiAn
authors.initials: Z
authors.lastname: Jiang
authors.forename: JunYing
authors.initials: J
authors.lastname: Zhou
authors.forename: DongFang
authors.initials: D
authors.lastname: Zhou
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: CaiYan
authors.initials: C
authors.lastname: Zhao
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhen
authors.forename: Amin A
authors.initials: AA
authors.lastname: Nanji
mesh_terms: D052242:Adiponectin / Q000032:analysis / Q000097:blood; D000818:Animals; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000009:adverse effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D047493:PPAR alpha / Q000032:analysis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017208:Rats, Wistar; D054419:Receptors, Adiponectin / Q000097:blood; D014157:Transcription Factors / Q000032:analysis
chemical_list: D052242:Adiponectin; D007004:Hypoglycemic Agents; D047493:PPAR alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D054419:Receptors, Adiponectin; D014157:Transcription Factors; C506573:adiponectin receptor 2, rat; D000431:Ethanol; D008687:Metformin
keywords: Adenosine Monophosphate-Activated Protein Kinase; Adiponectin; Ethanol; Insulin Resistance; Metformin