Metformin is a first-line drug for the treatment of individuals with type 2 diabetes, yet its precise mechanism of action remains unclear. Metformin exerts its antihyperglycemic action primarily through lowering hepatic glucose production (HGP). This suppression is thought to be mediated through inhibition of mitochondrial respiratory complex I, and thus elevation of 5′-adenosine monophosphate (AMP) levels and the activation of AMP-activated protein kinase (AMPK), though this proposition has been challenged given results in mice lacking hepatic AMPK. Here we report that the AMP-inhibited enzyme fructose-1,6-bisphosphatase-1 (FBP1), a rate-controlling enzyme in gluconeogenesis, functions as a major contributor to the therapeutic action of metformin. We identified a point mutation in FBP1 that renders it insensitive to AMP while sparing regulation by fructose-2,6-bisphosphate (F-2,6-P2), and knock-in (KI) of this mutant in mice significantly reduces their response to metformin treatment. We observe this during a metformin tolerance test and in a metformin-euglycemic clamp that we have developed. The antihyperglycemic effect of metformin in high-fat diet–fed diabetic FBP1-KI mice was also significantly blunted compared to wild-type controls. Collectively, we show a new mechanism of action for metformin and provide further evidence that molecular targeting of FBP1 can have antihyperglycemic effects.
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We thank M. Deak for molecular biology assistance and S. Jakobsen and J. Frøkiær for support in method development of the [11C]metformin-uptake study. We also thank E. Heikkilä for performing islet isolation, S. Ducommun for performing the pTBC1D1 blot, and S. Cotting for constructing Wollenberger tongs.GLUT2 antibody was provided by B. Thorens, GCK/HXK4 antibody was provided by M. Magnuson, GCKR antibody was provided by M. Shiota, G6PC antibody was provided by G. Mithieux, PFKFB1 antibody was provided by S. Baltrusch, pS33 PFKFB1 antibody was provided by J. Xie and pS8 GYS2 antibody was provided by J. Guinovart. This study was supported by Vanderbilt Mouse Metabolic Phenotyping Center Grant DK059637 (D.H.W.) and R37 DK050277 (D.H.W.), a Foundation Grant (FND 143277) from the Canadian Institutes of Health Research (F.S.), the Danish Council for Independent Research DFF—4183-00384 (N.J.) and the Novo Nordisk Foundation NNF13OC0003882 (N.J.). E.Z. was supported by a Sir Henry Wellcome postdoctoral fellowship. C.C.H. was supported by a Canadian Diabetes Association postdoctoral fellowship.
K.S. is a full-time employee of the Nestlé Institute of Health Sciences S.A., Switzerland.
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Hunter, R.W., Hughey, C.C., Lantier, L. et al. Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase. Nat Med 24, 1395–1406 (2018) doi:10.1038/s41591-018-0159-7
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