Cited by 1,181Metabolism, Diabetes, and CancerGlycogen Storage Diseases and MyoclonusNatural Antidiabetic Agents Studies

Metformin Inhibits Hepatic Gluconeogenesis in Mice Independently of the LKB1/AMPK Pathway via a Decrease in Hepatic Energy State

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Foretz, Marc, Hébrard, Sophie, Leclerc, Jocelyne, Zarrinpashneh, Elham, Soty, Maud, Mithieux, Gilles, Sakamoto, Kei, Andreelli, Fabrizio +1 more·2010·Journal of Clinical Investigation

Abstract

Metformin is widely used to treat hyperglycemia in individuals with type 2 diabetes. Recently the LKB1/AMP-activated protein kinase (LKB1/AMPK) pathway was proposed to mediate the action of metformin on hepatic gluconeogenesis. However, the molecular mechanism by which this pathway operates had remained elusive. Surprisingly, here we have found that in mice lacking AMPK in the liver, blood glucose levels were comparable to those in wild-type mice, and the hypoglycemic effect of metformin was maintained. Hepatocytes lacking AMPK displayed normal glucose production and gluconeogenic gene expression compared with wild-type hepatocytes. In contrast, gluconeogenesis was upregulated in LKB1-deficient hepatocytes. Metformin decreased expression of the gene encoding the catalytic subunit of glucose-6-phosphatase (G6Pase), while cytosolic phosphoenolpyruvate carboxykinase (Pepck) gene expression was unaffected in wild-type, AMPK-deficient, and LKB1-deficient hepatocytes. Surprisingly, metformin-induced inhibition of glucose production was amplified in both AMPK- and LKB1-deficient compared with wild-type hepatocytes. This inhibition correlated in a dose-dependent manner with a reduction in intracellular ATP content, which is crucial for glucose production. Moreover, metformin-induced inhibition of glucose production was preserved under forced expression of gluconeogenic genes through PPARgamma coactivator 1alpha (PGC-1alpha) overexpression, indicating that metformin suppresses gluconeogenesis via a transcription-independent process. In conclusion, we demonstrate that metformin inhibits hepatic gluconeogenesis in an LKB1- and AMPK-independent manner via a decrease in hepatic energy state.

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Research works printed but not linked: 3

  1. Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334(9):574-579.
  2. Kirpichnikov D, McFarlane SI, Sowers JR. Metfor- min: an update. Ann Intern Med. 2002;137(1):25-33.
  3. Sakamoto K, et al. Deficiency of LKB1 in heart pre- vents ischemia-mediated activation of AMPKal- pha2 but not AMPKalpha1. Am J Physiol Endocrinol Metab. 2006;290(5):E780-E788.

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Authors
Foretz, M., Hébrard, S., Leclerc, J., Zarrinpashneh, E., Soty, M., Mithieux, G., Sakamoto, K., Andreelli, F., & Viollet, B.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Institut Cochin (FR)
  • MRC Protein Phosphorylation and Ubiquitylation Unit (GB)
  • Nutrition, Diabète et Cerveau (FR)
Venue
Journal of Clinical Investigation
Published
2010-07-01
Volume
120
Issue
7
Pages
2355-2369
ISSN
0021-9738 (ISSN-L)
OpenAlex
W2092340120
Cited by
1,181
References
69
Citations by year
2026: 17 · 2025: 42 · 2024: 51 · 2023: 58 · 2022: 68 · 2021: 77 · 2020: 78 · 2019: 78 · 2018: 89 · 2017: 82 · 2016: 90 · 2015: 90 · 2014: 108 · 2013: 90 · 2012: 80
FWCI
32.98
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
Funders
  • University of Dundee
  • Diabetes UK (07/0003529)
  • European Commission (LSHMCT-2004-005272)
  • Agence Nationale de la Recherche (ANR-06-PHYS-0026)
  • Swedish Foundation for International Cooperation in Research and Higher Education
  • Association pour la Recherche sur le Diabète
  • U.S. Public Health Service (07/0003529)
  • Medical Research Council (07/0003529)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
Keywords
metformin, hepatic gluconeogenesis, LKB1, AMPK, intracellular ATP, glucose-6-phosphatase, phosphoenolpyruvate carboxykinase, PGC-1α, type 2 diabetes, hypoglycemic effect
MeSH terms
Animals, Diabetes Mellitus, Type 2, Gluconeogenesis, Glucose, Glucose-6-Phosphatase, Hyperglycemia, Hypoglycemic Agents, Liver, Metformin, Mice, Inbred C57BL, Up-Regulation, Protein Serine-Threonine Kinases, Mice, Knockout, Phosphoenolpyruvate Carboxykinase (ATP), Hepatocytes, Mice, AMP-Activated Protein Kinases

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