1. Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase-dependent regulation of the orphan nuclear receptor SHP
- Author
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Kim, Yong Deuk, Park, Keun-Gyu, Lee, Yong-Soo, Park, Yun-Yong, Kim, Don-Kyu, Nedumaran, Balachandar, Jang, Won Gu, Cho, Won-Jea, Ha, Joohun, Lee, In-Kyu, Lee, Chul-Ho, and Choi, Heung- Sik
- Subjects
Adenylic acid -- Genetic aspects -- Research -- Analysis -- Physiological aspects ,Drugs -- Structure-activity relationships ,Gene expression -- Analysis -- Research -- Physiological aspects -- Genetic aspects ,Structure-activity relationship (Pharmacology) -- Genetic aspects -- Research -- Analysis -- Physiological aspects ,Metformin -- Dosage and administration -- Physiological aspects -- Research ,Gluconeogenesis -- Prevention -- Physiological aspects -- Genetic aspects -- Analysis -- Research ,DNA binding proteins -- Genetic aspects -- Research -- Physiological aspects -- Analysis ,Health ,Prevention ,Physiological aspects ,Analysis ,Genetic aspects ,Research ,Dosage and administration - Abstract
OBJECTIVE--Metformin is an antidiabetic drug 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; NROB2). RESEARCH DESIGN AND METHODS--We assessed the regulation of hepatic SHP gene expression by Northern blot analysis with metformin and adenovirus containing a constitutive active form of AMP-activated protein kinase (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 metformin- and adenovirus SHP (Ad-SHP)mediated hepatic glucose production was measured in B6[Lep.sup.ob/ob] mice. RESULTS--Hepatic SHP gene expression was induced by metformin, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), and Ad-AMPK. Metformin-induced SHP gene expression was abolished by adenovirus containing the dominant negative form of AMPK (Ad-DN-AMPK), as well as by compound C. Metformin inhibited hepatocyte nuclear factor-4α- or FoxA2-mediated promoter activity of PEPCK and G6Pase, and the inhibition was blocked with siRNA SHP. Additionally, SHP knockdown by adenovirus containing siRNA SHP inhibited metformin-mediated repression of cAMP/dexamethasone-induced hepatic gluconeogenic gene expression. Furthermore, oral administration of metformin increased SHP mRNA levels in B6[Lep.sup.ob/ob] mice. Overexpression of SHP by Ad-SHP decreased blood glucose levels and hepatic gluconeogenic gene expression in B6-[Lep.sup.ob/ob] mice. CONCLUSIONS--We have concluded that metformin inhibits hepatic gluconeogenesis through AMPK-dependent regulation of SHP., Metformin (1,1-dimethylbiguanide hydrochloride) is a hypoglycemic agent used extensively for the treatment of type 2 diabetes (1-2). Metformin is a biguanide agent, as are buformin and phenformin. The principal function [...]
- Published
- 2008