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Nat Med. 2018 Sep;24(9):1395-1406. doi: 10.1038/s41591-018-0159-7. Epub 2018 Aug 27.

Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase.

Author information

1
Nestlé Institute of Health Sciences SA, Lausanne, Switzerland.
2
School of Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol, UK.
3
Department of Molecular Physiology and Biophysics and the Vanderbilt Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, TN, USA.
4
Departments of Clinical Medicine and Biomedicine, Aarhus University, Aarhus, Denmark.
5
MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, UK.
6
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
7
Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK.
8
Departments of Biochemistry and Molecular Genetics, University of Toronto, Toronto, ON, Canada.
9
Nestlé Institute of Health Sciences SA, Lausanne, Switzerland. kei.sakamoto@rd.nestle.com.

Abstract

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.

PMID:
30150719
PMCID:
PMC6207338
DOI:
10.1038/s41591-018-0159-7
[Indexed for MEDLINE]
Free PMC Article

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