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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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Role of AMP-Activated Protein Kinase in Mechanism of Metformin Action
Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci13505 · Cited by 5,652
AMPK: a nutrient and energy sensor that maintains energy homeostasis
Hardie, D. G., Ross, F. A., & Hawley, S. A. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3311 · Cited by 4,602
OWEN, M. R., DORAN, E., & HALESTRAP, A. P. (2000) · Biochemical Journal · doi:10.1042/bj3480607 · Cited by 2,157
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
LKB1 is the upstream kinase in the AMP-activated protein kinase cascade
Woods, A., Johnstone, S. R., Dickerson, K., Leiper, F. C., Fryer, L. G. D., Neumann, D., Schlattner, U., Wallimann, T., Carlson, M., & Carling, D. (2003) · Current Biology · doi:10.1016/j.cub.2003.10.031 · Cited by 1,650
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
El-Mir, M.-Y., Nogueira, V., Fontaine, E., Avéret, N., Rigoulet, M., & Leverve, X. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.1.223 · Cited by 1,399
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.
Hundal, R. S., Krssak, M., Dufour, S., Laurent, D., Lebon, V, Chandramouli, V, Inzucchi, S. E., Schumann, W. C., Petersen, K. F., Landau, B. R., et al. (2000) · Diabetes · doi:10.2337/diabetes.49.12.2063 · Cited by 1,052
Merrill, G. F., Kurth, E. J., Hardie, D. G., & Winder, W. W. (1997) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1997.273.6.e1107 · Cited by 1,048
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Llerena, P., Samarah, H., Nunes, K. L., Lin, Z., Bridgham, K., Tekumalla, S., Jain, A., Harshyne, L. A., Shukla, S. K., Vathiotis, I. A., et al. (2025) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-25-1098 · Cited by 8
“Metformin’s activity is also attributed to AMP kinase activation and inhibition of mitochondrial complex I (24, 25).”
Zhang, X.-Z., Sun, Y., Zhang, M.-H., & Jin, Z. (2022) · Folia Histochemica et Cytobiologica · doi:10.5603/fhc.a2022.0005 · Cited by 7
“Adenosine monophosphate-activated protein kinase (AMPK) is a heterotrimer composed of a catalytic subunit (α) and two regulatory subunits (β and γ) [7].”
BackgroundAchanta, L. B., Thomas, D. S., Housley, G. D., & Rae, C. D. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15815 · Cited by 6
“Evidence also suggests metformin promotes the assembly of the AMPK heterotrimeric complex, which in turn increases the phosphorylation of AMPK at Thr-172 by LKB1 and also decreases the dephosphorylation at Thr-172 by protein phosphatase 2C (Meng et al., 2015 ).”
BackgroundSOKOLOVA, L. K., PUSHKAREV, V. V., Belchina, Y. B., PUSHKAREV, V. V., & Tronko, M. D. (2018) · Reports of the National Academy of Sciences of Ukraine · doi:10.15407/dopovidi2018.05.100 · Cited by 9
“The latter fact is of particular interest, taking into account that the hyperglycemic effect of metformin is mainly related to the suppression of the glucose production in liver by activating the LKB1-AMPK pathway [6].”
BackgroundVirginia, D. M., Dwiprahasto, I., Wahyuningsih, M. S. H., & Nugrahaningsih, D. A. A. (2022) · Malaysian Journal of Medical Sciences · doi:10.21315/mjms2022.29.3.2 · Cited by 8
De, S., Banerjee, S., Rakshit, P., Banerjee, S., & Kumar, S. K. A. (2024) · Current Diabetes Reviews · doi:10.2174/0115733998291968240429111357 · Cited by 6
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PUSHKAREV, V. V., SOKOLOVA, L. K., PUSHKAREV, V. V., Belchina, Y. B., Вацеба, Т. С., & Tronko, M. D. (2019) · PROBLEMS OF ENDOCRINE PATHOLOGY · doi:10.21856/j-pep.2019.3.10 · Cited by 7
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SOKOLOVA, L. K., Пушкарьов, В. М., Бєльчина, Ю. Б., Пушкарьов, В. В., & Tronko, M. D. (2017) · Reports of the National Academy of Sciences of Ukraine · doi:10.15407/dopovidi2017.06.096 · Cited by 4
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Pearah, A., Ramatchandirin, B., Ramirez, K., Radovick, S., Wondisford, F. E., & He, L. (2025) · Endocrine Connections · doi:10.1530/ec-25-0260 · Cited by 5
Umekar, M. J., Qutub, M., Premchandani, T., Tatode, A., Taksansde, J., Singanwad, P., Kale, M. B., Maniyar, M. G., & Hussain, U. (2025) · Precision medication. · doi:10.1016/j.prmedi.2025.100051 · Cited by 4
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Kaushik, A. S., Agarwal, V., Kumar, N., Rehman, M., Chaudhary, R., Srivastava, S., Srivastava, S., & Mishra, V. (2025) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2025.151567 · Cited by 3
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Carman, L., Schuck, R. J., Li, E., & Nelson, M. D. (2022) · PubMed Central · doi:10.17912/micropub.biology.000596 · Cited by 3
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Alhowail, A. H., Alomran, A., Alqefari, N., Aldubayan, M. A., & Alenezi, S. K. (2023) · International Journal of Pharmacology · doi:10.3923/ijp.2023.505.513 · Cited by 2
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Yu, Q., Barndt, R. J., Shen, Y., Sallam, K., Tang, Y. M., Chan, S. Y., Wu, J. C., Liu, Q., & Wu, H. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.04.17.589921 · Cited by 1
Natural and Synthetic GHSR1a Agonists as Neuroprotective Agents in Models of Parkinson's disease
Rees, D. J. (2017) · Cronfa (Swansea University) · doi:10.23889/suthesis.40946
Río, A. G.-D. (2019) · UVaDOC UVaDOC University of Valladolid Documentary Repository (University of Valladolid) · doi:10.35376/10324/36270
McGarry, S. (2020) · uO Research (University of Ottawa) · doi:10.20381/ruor-25730
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Raikwar, A., & Vinode, P. K. (2023) · Advance Pharmaceutical Journal · doi:10.31024/apj.2023.8.4.1
Yu, Q., Shen, Y., Barndt, R. J., Sallam, K., Tang, Y. M., Brown, C. E., Li, X., Chan, S. Y., Wu, J. C., Liu, Q., et al. (2025) · Advanced Science · doi:10.1002/advs.202511480 · Cited by 1
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Haugaard, S. L., Schneider, M. J., Kjeldsen, S. T., Sattler, S. M., Bastrup, J., Saljic, A., Birk, J. B., Hansen, C., Synnestvedt, J. N., van Hunnik, A., et al. (2025) · Circulation Arrhythmia and Electrophysiology · doi:10.1161/circep.125.013850 · Cited by 2
Additional file 1 of Metformin alters therapeutic effects in the BALB/c tumor therapy model
Meyer, F. B., Goebel, S., Spangel, S. B., Leovsky, C., Hoelzer, D., & Thierbach, R. (2021) · Figshare · doi:10.6084/m9.figshare.14691850
Additional file 2 of Metformin alters therapeutic effects in the BALB/c tumor therapy model
Meyer, F. B., Goebel, S., Spangel, S. B., Leovsky, C., Hoelzer, D., & Thierbach, R. (2021) · Figshare · doi:10.6084/m9.figshare.14691853
Jan, I., Ali, T., Ali, R., Khan, N. U., Andrabi, K. I., & Bader, G. N. (2026) · Medical Oncology · doi:10.1007/s12032-026-03261-2
“After 24 h, cells were washed with PBS and stained with freshly prepared AO/EtBr solution (100 µg/mL each binding energy of − 6.8 kcal/mol (Table 1 ), which is con - sistent with previously reported binding energies, thereby validating the reliability of the docking workflow [ 12 ].”
InfluentialLiao, Y., Li, X., Liu, M., Fernandes, V. C., Duckett, D., Haura, E. B., Monastyrskyi, A., & Rix, U. (2026) · Cancer Research Communications · doi:10.1158/2767-9764.crc-25-0698
“Metformin is a well-known AMPK activator acting by the inhibition of complex 1 of the mitochondrial respiratory chain (40) and promoted formation of the AMPK αβγ complex at relatively low doses (41).”
BindingDB (2026) · UC San Diego · doi:10.7270/q2pr81tm
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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