계명대학교 의학도서관 Repository

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

Metadata Downloads
Author(s)
Yong Deuk KimKeun-Gyu ParkYong-Soo LeeYun-Yong ParkDon-Kyu KimBalachandar NedumaranWon Gu JangWon-Jea ChoJoohun HaIn-Kyu LeeChul-Ho LeeHueng-Sik Choi
Keimyung Author(s)
Park, Keun Gyu
Department
Dept. of Internal Medicine (내과학)
Journal Title
Diabetes
Issued Date
2008
Volume
57
Issue
2
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 metformininduced
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- -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-4 – 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. Diabetes 57:306–314, 2008
Keimyung Author(s)(Kor)
박근규
Publisher
School of Medicine
Citation
Yong Deuk Kim et al. (2008). Metformin Inhibits Hepatic Gluconeogenesis Through
AMP-Activated Protein Kinase–Dependent Regulation of
the Orphan Nuclear Receptor SHP. Diabetes, 57(2), 306–314. doi: 10.2337/db07-0381
Type
Article
ISSN
0012-1797
DOI
10.2337/db07-0381
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/35565
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Internal Medicine (내과학)
공개 및 라이선스
  • 공개 구분공개
파일 목록

Items in Repository are protected by copyright, with all rights reserved, unless otherwise indicated.