title: Metformin improves hepatic IRS2/PI3K/Akt signaling in insulin-resistant rats of NASH and cirrhosis.
abstract: Nonalcoholic fatty liver disease and cirrhosis are strongly associated with insulin resistance and glucose intolerance. To date, the influence of metformin on glycogen synthesis in the liver is controversial. Limited studies have evaluated the effect of metformin on hepatic insulin signaling pathway in vivo In this study, an insulin-resistant rat model of nonalcoholic steatohepatitis and cirrhosis was developed by high-fat and high-sucrose diet feeding in combination with subcutaneous injection of carbon tetrachloride. Liver tissues of the model rats were featured with severe steatosis and cirrhosis, accompanied by impaired liver function and antioxidant capacity. The glucose tolerance was impaired, and the index of insulin resistance was increased significantly compared with the control. The content of hepatic glycogen was dramatically decreased. The expression of insulin receptor β (IRβ); phosphorylations of IRβ, insulin receptor substrate 2 (IRS2), and Akt; and activities of phosphatidylinositol 3-kinase (PI3K) and glycogen synthase (GS) in the liver were significantly decreased, whereas the activities of glycogen synthase kinase 3α (GSK3α) and glycogen phosphorylase a (GPa) were increased. Metformin treatment remarkably improved liver function, alleviated lipid peroxidation and histological damages of the liver, and ameliorated glucose intolerance and insulin resistance. Metfromin also significantly upregulated the expression of IRβ; increased the phosphorylations of IRβ, IRS2, and Akt; increased the activities of PI3K and GS; and decreased GSK3α and GPa activities. In conclusion, our study suggests that metformin upregulates IRβ expression and the downstream IRS2/PI3K/Akt signaling transduction, therefore, to increase hepatic glycogen storage and improve insulin resistance. These actions may be attributed to the improved liver histological alterations by metformin.
authors.affiliation: Department of Gastroenterology and HepatologyHangzhou Red Cross Hospital, Hangzhou, China hongxuhzrc@aliyun.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Xu
authors.affiliation: Liver Cirrhosis SectionDepartment of Hepatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China Institute of Liver DiseasesShanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Clinical LaboratoryHangzhou Red Cross Hospital, Hangzhou, China.
authors.forename: Yongxia
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Liver Cirrhosis SectionDepartment of Hepatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China Institute of Liver DiseasesShanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Ping
authors.affiliation: Experimental Animal Research CenterZhejiang Chinese Medical University, Hangzhou, China.
authors.forename: Qiyang
authors.initials: Q
authors.lastname: Shou
authors.affiliation: Experimental Animal Research CenterZhejiang Chinese Medical University, Hangzhou, China.
authors.forename: Fangming
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of PathologyHangzhou Red Cross Hospital, Hangzhou, China.
authors.forename: Ru
authors.initials: R
authors.lastname: Ruo
mesh_terms: D000818:Animals; D018149:Glucose Intolerance / Q000188:drug therapy / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy* / Q000378:metabolism*; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007004:Hypoglycemic Agents; D055504:Insulin Receptor Substrate Proteins; C526299:Irs2 protein, rat; D008112:Liver Glycogen; D008687:Metformin; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt
keywords: IRS2/PI3K/Akt signaling pathway; cirrhosis; insulin resistance; metformin; nonalcoholic steatohepatitis