Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase dependent regulation of the orphan nuclear rec

Objective: Metformin is an antidiabetic drug which is commonly used to treat type 2 diabetes. The aim of the study was to determine whether metformin regulates hepatic gluconeogenesis through the orphan nuclear receptor small heterodimer partner (SHP; NR0B2). Research Design and Methods: We assessed the regulation of hepatic SHP gene expression by Northern blot analysis with metformin and adenovirus containing constitutive active form of AMPK (Ad-AMPK), and evaluated SHP, PEPCK, and G6Pase promoter activities via transient transfection assays in hepatocytes. Knockdown of SHP using siRNA SHP was conducted to characterize the metformin-induced inhibition of hepatic gluconeogenic gene expression in hepatocytes, and metforminand Ad-SHPmediated hepatic glucose production was measured in B6-Lep mice. Results: Hepatic SHP gene expression was induced by metformin, AICAR, and AdAMPK. Metformin-induced SHP gene expression was abolished by adenovirus containing dominant negative form of AMPK (Ad-DN AMPK), as well as by compound C. Metformin inhibited HNF-4αor FoxA2-mediated promoter activity of PEPCK, G6Pase, and the inhibition was blocked with siRNA SHP. Additionally, SHP knockdown by adenovirus containing siRNA SHP (Ad-siRNA SHP) inhibited metformin-mediated repression of cAMP/dexamethasone-induced hepatic gluconeogenic gene expression. Furthermore, oral administration of metformin increased SHP mRNA levels in B6Lep mice. Overexpression of SHP by Ad-SHP decreased blood glucose levels and hepatic gluconeogenic gene expression in B6-Lep mice. Conclusion: We have concluded that metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase dependent regulation of SHP.