The DOI matches its Crossref record; 85 of the 86 references it cites were found in a registry or an index.
Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase
Open accessAbstract
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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“metformin’s suppression of hepatic glucose production is shown to be the result of AMP-induced inhibition of fructose-1,6-bisphosphatase-1, a rate-controlling enzyme in gluconeogenesis”
From Benefits of Metformin in Attenuating the Hallmarks of Aging (2020) · cites this paper as Hunter et al. 2018
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New insights into activation and function of the AMPK
Steinberg, G. R., & Hardie, D. G. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-022-00547-x · Cited by 1,074
Cellular and Molecular Mechanisms of Metformin Action
LaMoia, T. E., & Shulman, G. I. (2021) · Endocrine Reviews · doi:10.1210/endrev/bnaa023 · Cited by 791
Benefits of Metformin in Attenuating the Hallmarks of Aging
Kulkarni, A. S., Gubbi, S., & Barzilai, N. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.04.001 · Cited by 766
Metformin: update on mechanisms of action and repurposing potential
Foretz, M., Guigas, B., & Viollet, B. (2023) · Nature Reviews Endocrinology · doi:10.1038/s41574-023-00833-4 · Cited by 791
Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus
Foretz, M., Guigas, B., & Viollet, B. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0242-2 · Cited by 686
Metadata
- 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
- Venue
- Nature Medicine
- Published
- 2018-08-27
- Volume
- 24
- Issue
- 9
- Pages
- 1395-1406
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- 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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