Cited by 319Metabolism, Diabetes, and CancerDiabetes Treatment and ManagementGlycogen Storage Diseases and Myoclonus

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

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Hunter, Roger W., Hughey, Curtis C., Lantier, Louise, Sundelin, Elias I., Peggie, Mark, Zeqiraj, Elton, Sicheri, Frank, Jessen, Niels, Wasserman, David H., Sakamoto, Kei·2018·Nature Medicine

DOI 10.1038/s41591-018-0159-7PMC PMC6207338

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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. The antidiabetic action of metformin raises heptocyte intracellular AMP levels, causing allosteric inhibition of fructose-1,6-bisphosphatase and thus reductions in gluconeogenesis.

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Authors: Hunter, R. W., Hughey, C. C., Lantier, L., Sundelin, E. I., Peggie, M., Zeqiraj, E., Sicheri, F., Jessen, N., Wasserman, D. H., & Sakamoto, K.
Affiliations: University of Bristol (GB)
Vanderbilt University (US)
Aarhus University (DK)
University of Dundee (GB)
Mount Sinai Hospital (CA)
Corresponding author: Sakamoto, Kei
ORCID: Hunter, Roger W.
Hughey, Curtis C.
Lantier, Louise
Sundelin, Elias I.
Peggie, Mark
Zeqiraj, Elton
Sicheri, Frank
Jessen, Niels
Wasserman, David H.
Sakamoto, Kei
Venue: Nature Medicine
Publisher: Springer Science and Business Media LLC
Published: 2018-08-27
Volume: 24
Issue: 9
Pages: 1395-1406
ISSN: 1078-8956 (ISSN-L)
1546-170X
DOI: 10.1038/s41591-018-0159-7
PMC: PMC6207338
OpenAlex: W2888330909
Cited by: 313
References: 86
Citations by year: 2026: 25 · 2025: 33 · 2024: 47 · 2023: 53 · 2022: 49 · 2021: 33 · 2020: 43 · 2019: 26 · 2018: 4
FWCI: 9.51
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
Locations: Nature Medicine (publishedVersion)
PubMed (publishedVersion)
Discovery Research Portal (University of Dundee) (publishedVersion)
Explore Bristol Research (publishedVersion, other-oa)
White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Bristol Research (University of Bristol) (submittedVersion, other-oa)
Funders: Vanderbilt University (DK059637)
Wellcome Trust (092381)
Novo Nordisk
Danmarks Frie Forskningsfond (4183-00384)
Novo Nordisk Fonden (NNF13OC0003882, NNF17SA0031230-1)
Canadian Institutes of Health Research (143277)
National Institute of Diabetes and Digestive and Kidney Diseases (U2CDK059637, U24DK059637, R37DK050277, P30DK058404)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Glycogen Storage Diseases and Myoclonus
Keywords: metformin, FBP1, hepatic glucose production, gluconeogenesis, AMPK, fructose-2,6-bisphosphate, type 2 diabetes, high-fat diet, euglycemic clamp
MeSH terms: Adenosine Monophosphate, Aminoimidazole Carboxamide, Animals, Base Sequence, Chickens, Disease Models, Animal, Glucose, Fructose-Bisphosphatase, Homeostasis, Humans, Hypoglycemia, Liver, Metformin, Mice, Inbred C57BL, Mutation, Obesity, Prodrugs, Ribonucleotides, Glucose Intolerance

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

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