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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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“Metformin, in addition to its antidiabetic effects, has been reported to protect mice with MASLD by reducing liver fat accumulation and improving insulin sensitivity through the regulation of the AMPK/mTOR pathway, as it activates AMPK and thereby inhibits mTORC1 [178,179].”
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Zhang, M., Fang, X.-S., Guo, J., & Jin, Z. (2019) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-019-00870-9 · Cited by 17
Natarajan, V., Mah, T. K. L., Chen, P., Tan, S., Chawla, R., Arumugam, T. V., Ramasamy, A., & Mallilankaraman, K. B. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.533683 · Cited by 16
“Frontiers in Physiology | www.frontiersin.org 11 September 2020 | Volume 11 | Article 533683 Endothelial cells migrate during angiogenesis, but they do migrate under pathophysiological conditions to restore vascular integrity (Michaelis, 2014).”
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Bioactive compounds, pharmacological actions and pharmacokinetics of Cupressus sempervirens
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Modulating Phosphorylation by Proximity-Inducing Modalities for Cancer Therapy
Zhang, Q., Yu, J., You, Q., & Wang, L. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c02624 · Cited by 15
Metformin Effects on SHIP2, AMPKs and Gut Microbiota: Recent Updates on Pharmacology
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Metformin improves Mycobacterium avium infection by strengthening macrophage antimicrobial functions
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“The drug is already well known to activate adenosine-monophosphate (AMP)-activated kinase (AMPK) by increasing the phosphorylation of AMPK-α at Thr-172 [65].”
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“Several studies in primary hepatocytes have reported that metformin hydrochloride suppresses glucose production through the activation of AMPK signaling pathway (Cao et al., 2014; Meng et al., 2015; Zhou et al., 2001).”
BackgroundMetformin—mechanisms of its glycemia-reducing effect
Drewe, J., Foretz, M., & Krähenbühl, S. (2025) · Pharmacological Reviews · doi:10.1016/j.pharmr.2025.100106 · Cited by 18
Repurposing Metformin for the Treatment of Atrial Fibrillation: Current Insights
Sarkar, A., Fanous, K., Marei, I., Ding, H., Ladjimi, M. M., MacDonald, R. S., Hollenberg, M. D., Anderson, T. J., Hill, M. A., & Triggle, C. R. (2024) · Vascular Health and Risk Management · doi:10.2147/vhrm.s391808 · Cited by 11
“85–90 Another alternative pathway is activation of AMPK via a mechanism dependent on the expression of the Nuclear Receptor Subfamily 4 Group A Member 1, NR4A1 (also referred to Nur77), and subsequent activation of the STK11/AMPK signaling cascade.”
BackgroundChanging ROS, NAD and AMP: A path to longevity via mitochondrial therapeutics
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Hwang, S., Choi, Y., Wang, J., & Son, C. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116250 · Cited by 11
Mechanisms of Action of Metformin
Mahmood, S. A. (2021) · IntechOpen eBooks · doi:10.5772/intechopen.99189 · Cited by 10
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Therapeutically relevant natural products as AMPK activators in the treatment of diabetes
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Beneficial effects of metformin on glomerular podocytes in diabetes
Rogacka, D., & Piwkowska, A. (2021) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114687 · Cited by 10
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“The in vivo results indicated that compounds 4–6 may be effective in treating experimental T2DM.”
BackgroundInfluentialImpact of currently used anti-diabetic drugs on myoendothelial communication
Ding, H., Ye, K., & Triggle, C. R. (2018) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2018.11.002 · Cited by 9
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Trisal, A., & Singh, A. K. (2025) · Neuroscience · doi:10.1016/j.neuroscience.2025.01.004 · Cited by 9
Metformin: Antidiabetic actions from cells to tissues
Bailey, C. J., Gwilt, M., & Brand, K. M. G. (2026) · Metabolism · doi:10.1016/j.metabol.2026.156589 · Cited by 10
Mitra, A., Das, A., Ghosh, S., Sarkar, S., Bandyopadhyay, D., Gangopadhyay, S., & Chattopadhyay, S. (2024) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2024.167313 · Cited by 8
Pușcașu, C., Ungurianu, A., Șeremet, O. C., Andrei, C., Mihai, D. P., & Negreș, S. (2023) · Medicina · doi:10.3390/medicina59081375 · Cited by 8
“A diversity of cellular processes are regulated by AMPK, including mitochondrial metabolism, protein translation, and the activity of other kinases, many of which are implicated in the development of neuropathic pain [59,60].”
Background
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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