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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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“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).”
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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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