title: Berberine inhibits hepatic gluconeogenesis via the LKB1-AMPK-TORC2 signaling pathway in streptozotocin-induced diabetic rats.
abstract: OBJECTIVE
  To investigate the molecular mechanisms of berberine inhibition of hepatic gluconeogenesis in a diabetic rat model.
  
  
  METHODS
  The 40 rats were randomly divided into five groups. One group was selected as the normal group. In the remaining groups (n = 8 each), the rats were fed on a high-fat diet for 1 mo and received intravenous injection of streptozotocin for induction of the diabetic models. Berberine (156 mg/kg per day) (berberine group) or metformin (184 mg/kg per day) (metformin group) was intragastrically administered to the diabetic rats and 5-aminoimidazole-4-carboxamide1-β-D-ribofuranoside (AICAR) (0.5 mg/kg per day) (AICAR group) was subcutaneously injected to the diabetic rats for 12 wk. The remaining eight diabetic rats served as the model group. Fasting plasma glucose and insulin levels as well as lipid profile were tested. The expressions of proteins were examined by western blotting. The nuclear translocation of CREB-regulated transcription co-activator (TORC)2 was observed by immunohistochemical staining.
  
  
  RESULTS
  Berberine improved impaired glucose tolerance and decreased plasma hyperlipidemia. Moreover, berberine decreased fasting plasma insulin and homeostasis model assessment of insulin resistance (HOMA-IR). Berberine upregulated protein expression of liver kinase (LK)B1, AMP-activated protein kinase (AMPK) and phosphorylated AMPK (p-AMPK). The level of phophorylated TORC2 (p-TORC2) protein in the cytoplasm was higher in the berberine group than in the model group, and no significant difference in total TORC2 protein level was observed. Immunohistochemical staining revealed that more TORC2 was localized in the cytoplasm of the berberine group than in the model group. Moreover, berberine treatment downregulated protein expression of the key gluconeogenic enzymes (phosphoenolpyruvate carboxykinase and glucose-6-phosphatase) in the liver tissues.
  
  
  CONCLUSIONS
  Our findings revealed that berberine inhibited hepatic gluconeogenesis via the regulation of the LKB1-AMPK-TORC2 signaling pathway.
authors.affiliation: Shu-Jun Jiang, Hui Dong, Li-Jun Xu, Xin Zou, Kai-Fu Wang, Fu-Er Lu, Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
authors.forename: Shu-Jun
authors.initials: SJ
authors.lastname: Jiang
authors.affiliation: Shu-Jun Jiang, Hui Dong, Li-Jun Xu, Xin Zou, Kai-Fu Wang, Fu-Er Lu, Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Dong
authors.affiliation: Shu-Jun Jiang, Hui Dong, Li-Jun Xu, Xin Zou, Kai-Fu Wang, Fu-Er Lu, Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
authors.forename: Jing-Bin
authors.initials: JB
authors.lastname: Li
authors.affiliation: Shu-Jun Jiang, Hui Dong, Li-Jun Xu, Xin Zou, Kai-Fu Wang, Fu-Er Lu, Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Xu
authors.affiliation: Shu-Jun Jiang, Hui Dong, Li-Jun Xu, Xin Zou, Kai-Fu Wang, Fu-Er Lu, Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zou
authors.affiliation: Shu-Jun Jiang, Hui Dong, Li-Jun Xu, Xin Zou, Kai-Fu Wang, Fu-Er Lu, Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
authors.forename: Kai-Fu
authors.initials: KF
authors.lastname: Wang
authors.affiliation: Shu-Jun Jiang, Hui Dong, Li-Jun Xu, Xin Zou, Kai-Fu Wang, Fu-Er Lu, Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
authors.forename: Fu-Er
authors.initials: FE
authors.lastname: Lu
authors.affiliation: Shu-Jun Jiang, Hui Dong, Li-Jun Xu, Xin Zou, Kai-Fu Wang, Fu-Er Lu, Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yi
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001599:Berberine / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D005943:Gluconeogenesis / Q000187:drug effects*; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D006949:Hyperlipidemias / Q000188:drug therapy / Q000201:enzymology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008687:Metformin / Q000494:pharmacology; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017208:Rats, Wistar; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013311:Streptozocin; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; C545700:CRTC2 protein, rat; D007004:Hypoglycemic Agents; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids; D012265:Ribonucleotides; D015534:Trans-Activators; D001599:Berberine; D000620:Aminoimidazole Carboxamide; D013311:Streptozocin; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; C488755:Stk11 protein, rat; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D005952:Glucose-6-Phosphatase; C582554:Pck1 protein, rat; D010729:Phosphoenolpyruvate Carboxykinase (GTP); C031143:AICA ribonucleotide
keywords: AMPK; Berberine; Diabetes; Hepatic gluconeogenesis; LKB1; TORC2