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Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state
Marc Foretz, … , Fabrizio Andreelli, Benoit Viollet
Marc Foretz, … , Fabrizio Andreelli, Benoit Viollet
Published June 23, 2010
Citation Information: J Clin Invest. 2010;120(7):2355-2369. https://doi.org/10.1172/JCI40671.
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Research Article Article has an altmetric score of 17

Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state

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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 PPARγ coactivator 1α (PGC-1α) 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.

Authors

Marc Foretz, Sophie Hébrard, Jocelyne Leclerc, Elham Zarrinpashneh, Maud Soty, Gilles Mithieux, Kei Sakamoto, Fabrizio Andreelli, Benoit Viollet

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Figure 2

Effects of metformin on blood glucose levels in AMPKα1α2LS–/– mice.

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Effects of metformin on blood glucose levels in AMPKα1α2LS–/– mice.
   
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(A) Western blot analysis of AMPKα and PEPCK proteins in livers from 24-hour-fasted control and AMPKα1α2LS–/– mice. β-Actin was immunoblotted as a loading control. Each lane represents the liver sample from an individual mouse. (B) Plasma blood glucose levels were measured in fasted and fed control and AMPKα1α2LS–/– mice. n = 5–6. (C) Plasma insulin levels were measured in fasted and fed control and AMPKα1α2LS–/– mice. Data are mean ± SEM (n = 5–6). (D) Pyruvate tolerance tests (2 g/kg) in control and AMPKα1α2LS–/– mice were used to assess hepatic gluconeogenesis. n = 6–7. (E) Insulin tolerance tests (0.25 U/kg) in control and AMPKα1α2LS–/– mice. n = 6–9. Metformin tolerance tests in control (F) and AMPKα1α2LS–/– (G) mice. Mice were given an oral gavage dose of 50, 150, or 300 mg/kg metformin or vehicle and after 30 minutes challenged with an oral administration of glucose (3 g/kg body weight). n = 6–10. Data are mean ± SEM. *P < 0.05, **P < 0.005, 150 mg/kg metformin compared with vehicle control; #P < 0.01, ##P < 0.001, 300 mg/kg compared with the vehicle control.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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