Metformin Inhibits Hepatic Gluconeogenesis Through AMP-Activated Protein Kinase–Dependent Regulation of the Orphan Nuclear Receptor SHP
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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.
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Metformin activates AMPK and inhibits expression of the hepatic gluconeogenic genes PEPCK and G-6-Pase similarly to insulin.
“Metformin has been shown to activate AMPK and to inhibit the expression of the hepatic gluconeogenic genes PEPCK and G-6-Pase similarly to insulin (19).”
From Hypoglycemic effects of brassinosteroid in diet-induced obese mice (2012) · cites this paper as [19]
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- Authors
- Kim, Y. D., Park, K.-G., Lee, Y.-S., Park, Y.-Y., Kim, D.-K., Nedumaran, B., Jang, W. G., Cho, W.-J., Ha, J., Lee, I.-K., Lee, C.-H., & Choi, H.-S.
- Affiliations
- Chonnam National University (KR)
- Keimyung University (KR)
- Kyungpook National University (KR)
- Kyung Hee University (KR)
- Korea Research Institute of Bioscience and Biotechnology (KR)
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2008-02-01
- Volume
- 57
- Issue
- 2
- Pages
- 306-314
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2148672071
- Cited by
- 422
- References
- 39
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 10 · 2023: 21 · 2022: 12 · 2021: 19 · 2020: 27 · 2019: 18 · 2018: 18 · 2017: 28 · 2016: 26 · 2015: 30 · 2014: 35 · 2013: 32 · 2012: 41
- FWCI
- 7.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- KRIBB Repository (submittedVersion)
- KUMeL Repository (Keimyung University) (submittedVersion, cc-by-nc-nd)
- Funders
- Korea Science and Engineering Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
- Keywords
- metformin, hepatic gluconeogenesis, AMPK, small heterodimer partner, NR0B2, orphan nuclear receptor, phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, HNF4α, FOXA2, type 2 diabetes, hepatic glucose production, ob/ob mice
- MeSH terms
- Animals, Gluconeogenesis, Carcinoma, Hepatocellular, Humans, Hypoglycemic Agents, Liver, Liver Neoplasms, Male, Metformin, Multienzyme Complexes, Transfection, Rats, Sprague-Dawley, Protein Serine-Threonine Kinases, Receptors, Cytoplasmic and Nuclear, Hepatocytes, RNA, Small Interfering, Cell Line, Tumor, Rats, AMP-Activated Protein Kinases
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