The DOI matches its Crossref record; 47 of the 48 references it cites were found in a registry or an index.
Metformin Inhibits Hepatic mTORC1 Signaling via Dose-Dependent Mechanisms Involving AMPK and the TSC Complex
Open accessAbstract
Metformin is the most widely prescribed drug for the treatment of type 2 diabetes. However, knowledge of the full effects of metformin on biochemical pathways and processes in its primary target tissue, the liver, is limited. One established effect of metformin is to decrease cellular energy levels. The AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) are key regulators of metabolism that are respectively activated and inhibited in acute response to cellular energy depletion. Here we show that metformin robustly inhibits mTORC1 in mouse liver tissue and primary hepatocytes. Using mouse genetics, we find that at the lowest concentrations of metformin that inhibit hepatic mTORC1 signaling, this inhibition is dependent on AMPK and the tuberous sclerosis complex (TSC) protein complex (TSC complex). Finally, we show that metformin profoundly inhibits hepatocyte protein synthesis in a manner that is largely dependent on its ability to suppress mTORC1 signaling.
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“Of significance is that metformin, like rapamycin, is known to inhibit mTOR signaling, and the inhibition of the mTOR signaling pathway with rapamycin has been shown to extend lifespan in C. elegans, S. cerevisiae, and Drosophila melanogaster (fruit fly) (221–225).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [225]
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“Of significance is that metformin, like rapamycin, is known to inhibit mTOR signaling, and the inhibition of the mTOR signaling pathway with rapamycin has been shown to extend lifespan in C. elegans, S. cerevisiae, and Drosophila melanogaster (fruit fly) (221–225).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [225]
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Cites
mTOR Signaling in Growth Control and Disease
Laplante, M., & Sabatini, D. M. (2012) · Cell · doi:10.1016/j.cell.2012.03.017 · Cited by 8,509
Role of AMP-Activated Protein Kinase in Mechanism of Metformin Action
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TSC2 Mediates Cellular Energy Response to Control Cell Growth and Survival
Inoki, K., Zhu, T., & Guan, K.-L. (2003) · Cell · doi:10.1016/s0092-8674(03)00929-2 · Cited by 3,914
AMPK Phosphorylation of Raptor Mediates a Metabolic Checkpoint
Gwinn, D. M., Shackelford, D. B., Egan, D. F., Mihaylova, M. M., Mery, A., Vasquez, D. S., Turk, B. E., & Shaw, R. J. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.03.003 · Cited by 3,849
Self-citationWatterson, K. R., Bestow, D., Gallagher, J. R., Hamilton, D. L., Ashford, F. B., Meakin, P. J., & Ashford, M. L. J. (2012) · Neurosignals · doi:10.1159/000334144 · Cited by 3,395
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The Kinase LKB1 Mediates Glucose Homeostasis in Liver and Therapeutic Effects of Metformin
Shaw, R. J., Lamia, K. A., Vasquez, D., Koo, S.-H., Bardeesy, N., DePinho, R. A., Montminy, M., & Cantley, L. C. (2005) · Science · doi:10.1126/science.1120781 · Cited by 1,950
Self-citationAbsence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity
Um, S. H., Frigerio, F., Watanabe, M., Picard, F., Joaquin, M., Sticker, M., Fumagalli, S., Allegrini, P. R., Kozma, S. C., Auwerx, J., et al. (2004) · Nature · doi:10.1038/nature02866 · Cited by 1,677
Research works printed but not linked: 1
- Postic, 2000, DNA excision in liver by an albumin-Cre transgene occurs progressively with age, Genesis, 26, 149, 10.1002/(SICI)1526-968X(200002)26:2<149::AID-GENE16>3.0.CO;2-V · DOI
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Karimi, M., Hooshmand, F., Mohammadian, K., Pourfaraji, S. M., & Mortezazadeh, M. (2026) · Cancer Reports · doi:10.1002/cnr2.70651
Suárez-Barrios, V. W., Hernández-Alba, A. L., Juárez-Rojas, J. G., & Arellano-Buendía, A. S. (2026) · Plants · doi:10.3390/plants15172710
“AMPK can inhibit mammalian target of rapamycin complex 1 (mTORC1) signaling under conditions of cellular energy stress, thereby linking energy availability with anabolic metabolism [23,26].”
Chen, S., Lu, J., Gao, X., Guo, Z., Li, Y., Neema, U.-P., Fahad, A., Xu, X., Sun, Q., Zhang, C., et al. (2026) · Chemical Engineering Journal · doi:10.1016/j.cej.2026.181297
VijayaKumar, K., Mathur, N., Das, D., Chaudhary, A., Varadhan, P., Mishra, S. K., & Ramachandiran, S. (2026) · In Silico Research in Biomedicine · doi:10.1016/j.insi.2026.100638
Bartoszewicz, M., & Niemczyk, M. (2026) · Aging · doi:10.18632/aging.206426
Female microglia show heightened responses to aging and amyloid pathology in mice and humansPreprint
Cox, J. E. J., Poljanska, E., Ray, S., Forsgren, M., Ko, S.-H., Świergiel, P., Wright, Z., Thomas, M. A., Freeman, W. M., Nouh, C. D., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.10.13.758897
肖青, Li, S., Gan, Y., Xiao, J., Liu, J., Lei, H., Wen, H., Zhou, Z., Wu, J., Yi, H., et al. (2026) · 中国科学通报：英文版 · doi:10.1016/j.scib.2026.10.064
Metadata
- Authors
- Howell, J. J., Hellberg, K., Turner, M., Talbott, G., Kolar, M. J., Ross, D. S., Hoxhaj, G., Saghatelian, A., Shaw, R. J., & Manning, B. D.
- Affiliations
- Harvard University (US)
- Salk Institute for Biological Studies (US)
- Corresponding author
- Shaw, Reuben J.
- Manning, Brendan D.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-02
- Volume
- 25
- Issue
- 2
- Pages
- 463-471
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5299044
- OpenAlex
- W2572741715
- Cited by
- 408
- References
- 48
- Citations by year
- 2026: 24 · 2025: 40 · 2024: 61 · 2023: 42 · 2022: 47 · 2021: 49 · 2020: 62 · 2019: 42 · 2018: 25 · 2017: 16
- FWCI
- 16.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Ellison Medical Foundation
- NIH (F32-DK095508, F30-DK112604, R01-DK080425, P01-CA120964)
- George E. Hewitt Foundation for Medical Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- metformin, mTORC1 signaling, AMPK, tuberous sclerosis complex, liver, hepatocytes, protein synthesis, type 2 diabetes, dose-dependent effects
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Animals, Dose-Response Relationship, Drug, Humans, Liver, Metformin, Mice, Inbred C57BL, Organ Specificity, Protein Biosynthesis, Tuberous Sclerosis, Signal Transduction, Mice, Knockout, Hepatocytes, Multiprotein Complexes, AMP-Activated Protein Kinases, TOR Serine-Threonine Kinases
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