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Metformin lowers glucose 6-phosphate in hepatocytes by activation of glycolysis downstream of glucose phosphorylation

Lookup NU author(s): Tabassum Moonira, Dr Shruti Chachra, Dr Brian FordORCiD, Ahmed Alshawi, Dr Catherine ArdenORCiD, Dr Ziad Al-Oanzi, Professor Loranne Agius



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


The chronic effects of metformin on liver gluconeogenesis involve repression of the G6pc gene, which is regulated by the carbohydrate-response element–binding protein through raised cellular intermediates of glucose metabolism. In this study we determined the candidate mechanisms by which metformin lowers glucose 6-phosphate (G6P) in mouse and rat hepatocytes challenged with high glucose or gluconeogenic precursors. Cell metformin loads in the therapeutic range lowered cell G6P but not ATP and decreased G6pc mRNA at high glucose. The G6P lowering by metformin was mimicked by a complex 1 inhibitor (rotenone) and an uncoupler (dinitrophenol) and by overexpression of mGPDH, which lowers glycerol 3-phosphate and G6P and also mimics the G6pc repression by metformin. In contrast, direct allosteric activators of AMPK (A-769662, 991, and C-13) had opposite effects from metformin on glycolysis, gluconeogenesis, and cell G6P. The G6P lowering by metformin, which also occurs in hepatocytes from AMPK knockout mice, is best explained by allosteric regulation of phosphofructokinase-1 and/or fructose bisphosphatase-1, as supported by increased metabolism of [3-3H]glucose relative to [2-3H]glucose; by an increase in the lactate m2/m1 isotopolog ratio from [1,2-13C2]glucose; by lowering of glycerol 3-phosphate an allosteric inhibitor of phosphofructokinase-1; and by marked G6P elevation by selective inhibition of phosphofructokinase-1; but not by a more reduced cytoplasmic NADH/NAD redox state. We conclude that therapeutically relevant doses of metformin lower G6P in hepatocytes challenged with high glucose by stimulation of glycolysis by an AMP-activated protein kinase–independent mechanism through changes in allosteric effectors of phosphofructokinase-1 and fructose bisphosphatase-1, including AMP, Pi, and glycerol 3-phosphate.

Publication metadata

Author(s): Moonira T, Chachra SS, Ford BE, Marin S, Alshawi A, Adam-Primus NS, Arden C, Al-Oanzi ZH, Foretz M, Viollet B, Cascante M, Agius L

Publication type: Article

Publication status: Published

Journal: Journal of Biological Chemistry

Year: 2020

Volume: 295

Issue: 10

Pages: 3330-3346

Print publication date: 06/03/2020

Online publication date: 23/01/2020

Acceptance date: 23/01/2020

Date deposited: 06/03/2020

ISSN (print): 0021-9258

ISSN (electronic): 1083-351X

Publisher: American Society for Biochemistry and Molecular Biology


DOI: 10.1074/jbc.RA120.012533


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Funder referenceFunder name
MR/P002854/1Medical Research Council (MRC)