Metformin Inhibits Hepatic Gluconeogenesis Through AMP-Activated Protein Kinase–Dependent Regulation of the Orphan Nuclear Receptor SHP

  1. Yong Deuk Kim1,
  2. Keun-Gyu Park2,
  3. Yong-Soo Lee1,
  4. Yun-Yong Park1,
  5. Don-Kyu Kim1,
  6. Balachandar Nedumaran1,
  7. Won Gu Jang3,
  8. Won-Jea Cho4,
  9. Joohun Ha5,
  10. In-Kyu Lee3,
  11. Chul-Ho Lee6 and
  12. Hueng-Sik Choi1
  1. 1Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea
  2. 2Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea
  3. 3Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea
  4. 4College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju, Korea
  5. 5Department of Biochemistry and Molecular Biology, Medical Research Center for Bioreation to Reactive Oxygen Species, Kyung Hee University College of Medicine, Seoul, Republic of Korea
  6. 6Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
  1. Address correspondence and reprint requests to Hueng-Sik Choi, PhD, Hormone Research Center, School of Biological Sciences & Technology, Chonnam National University, Gwangju, 500-757, Republic of Korea. E-mail: hsc{at}chonnam.ac.kr

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; NR0B2).

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-Lepob/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-Lepob/ob mice. Overexpression of SHP by Ad-SHP decreased blood glucose levels and hepatic gluconeogenic gene expression in B6-Lepob/ob mice.

CONCLUSIONS—We have concluded that metformin inhibits hepatic gluconeogenesis through AMPK-dependent regulation of SHP.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 1 October 2007. DOI: 10.2337/db07-0381.

  • Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0381.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted September 26, 2007.
    • Received March 20, 2007.
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  1. Diabetes vol. 57 no. 2 306-314
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