The DOI matches its Crossref record; 40 of the 40 references it cites were found in a registry or an index.
Metformin Activates AMP-activated Protein Kinase by Promoting Formation of the αβγ Heterotrimeric Complex
Open accessAbstract
Metformin is the most widely prescribed oral anti-diabetic agent. Recently, we have shown that low metformin concentrations found in the portal vein suppress glucose production in hepatocytes through activation of AMPK. Moreover, low concentrations of metformin were found to activate AMPK by increasing the phosphorylation of AMPKα at Thr-172. However, the mechanism underlying the increase in AMPKα phosphorylation at Thr-172 and activation by metformin remains unknown. In the current study, we find that low concentrations of metformin promote the formation of the AMPK αβγ complex, resulting in an increase in net phosphorylation of the AMPK α catalytic subunit at Thr-172 by augmenting phosphorylation by LKB1 and antagonizing dephosphorylation by PP2C. Background: The mechanism underlying the activation of AMPK by metformin remains unclear. Results: Metformin promotes the formation of AMPK αβγ heterotrimeric complex. Conclusion: The formation of the AMPK αβγ heterotrimeric complex augments AMPKα phosphorylation by LKB1 and prevents dephosphorylation by protein phosphatase. Significance: Metformin-mediated formation of the AMPK αβγ heterotrimeric complex results in AMPK activation by elevating AMPK phosphorylation at Thr-172.
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“activation of AMPK by metformin has been observed at much lower metformin concentrations in comparable cell culture protocols using metformin concentrations that are within the upper limits of its therapeutic plasma levels (4, 134).”
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 [134]
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Role of AMP-Activated Protein Kinase in Mechanism of Metformin Action
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AMPK: a nutrient and energy sensor that maintains energy homeostasis
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The Kinase LKB1 Mediates Glucose Homeostasis in Liver and Therapeutic Effects of Metformin
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LKB1 is the upstream kinase in the AMP-activated protein kinase cascade
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Metformin improves healthspan and lifespan in mice
Martin-Montalvo, A., Mercken, E. M., Mitchell, S. J., Palacios, H. H., Mote, P. L., Scheibye-Knudsen, M., Gomes, A. P., Ward, T. M., Minor, R. K., Blouin, M.-J., et al. (2013) · Nature Communications · doi:10.1038/ncomms3192 · Cited by 1,445
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LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR‐1
Lizcano, J. M., Göransson, O., Toth, R., Deak, M., Morrice, N. A., Boudeau, J., Hawley, S. A., Udd, L., Mäkelä, T. P., Hardie, D. G., et al. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600110 · Cited by 1,381
Mechanism by which metformin reduces glucose production in type 2 diabetes.
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Metformin Improves Mitochondrial Respiratory Activity through Activation of AMPK
Wang, Y., An, H., Liu, T., Qin, C., Sesaki, H., Guo, S., Radovick, S., Hussain, M., Maheshwari, A., Wondisford, F. E., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.09.070 · Cited by 432
“We reported that metformin activates AMPK by promoting the formation of the functional AMPKαβγ heterotrimeric complex and phosphorylation of the CREB-binding protein (He et al., 2009, 2014; Meng et al., 2015).”
BackgroundSelf-citationTiberi, S., du Plessis, N., Walzl, G., Vjecha, M. J., Rao, M., Ntoumi, F., Mfinanga, S., Kapata, N., Mwaba, P., McHugh, T. D., et al. (2018) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(18)30110-5 · Cited by 403
Kelly, B., Tannahill, G. M., Murphy, M. P., & O'Neill, L. A. J. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.662114 · Cited by 334
Unraveling the regulation of hepatic gluconeogenesis
Zhang, X., Yang, S., Chen, J., & Su, Z. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00802 · Cited by 314
“There is evidence that metformin could promote the assembly of a functional AMPKαβγ heterotrimeric complex, making it more easily phosphorylated at T172 of subunit α1 by upstream kinase LKB1, as well as hindering the dephosphorylation of the T172 by protein phosphatase (121).”
BackgroundMetformin limits osteoarthritis development and progression through activation of AMPK signalling
Li, J., Zhang, B., Liu, W., Lu, K., Pan, H., Wang, T., Oh, C., Yi, D., Huang, J. H., Zhao, L., et al. (2020) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2019-216713 · Cited by 308
Metadata
- Authors
- Meng, S., Cao, J., He, Q., Xiong, L., Chang, E., Radovick, S., Wondisford, F. E., & He, L.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- He, Ling
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 290
- Issue
- 6
- Pages
- 3793-3802
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4319043
- OpenAlex
- W2013331748
- Cited by
- 146
- References
- 40
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 12 · 2023: 11 · 2022: 16 · 2021: 15 · 2020: 15 · 2019: 17 · 2018: 11 · 2017: 9 · 2016: 9 · 2015: 6
- FWCI
- 3.28
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (R00DK085142, R01DK63349)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- metformin, AMPK, AMPK activation, LKB1, protein phosphatase 2C, glucose production, hepatocytes, antidiabetic drugs
- MeSH terms
- Animals, Cells, Cultured, Hypoglycemic Agents, Metformin, Phosphorylation, Protein Binding, Protein Serine-Threonine Kinases, Protein Subunits, Hepatocytes, Cell Line, Tumor, Mice, Protein Phosphatase 2, AMP-Activated Protein Kinases, Protein Multimerization
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