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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Activation of AMPK by metformin has been observed at much lower metformin concentrations in comparable cell culture protocols using concentrations within the upper limits of therapeutic plasma levels.
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
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 · see citing works
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 · see citing works
OWEN, M. R., DORAN, E., & HALESTRAP, A. P. (2000) · Biochemical Journal · doi:10.1042/bj3480607 · Cited by 2,157 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 1,027 · see citing works
The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism
Koo, S., Flechner, L., Qi, L., Zhang, X., Screaton, R. A., Jeffries, S., Hedrick, S. A., Xu, W., Boussouar, F., Brindle, P. K., et al. (2005) · Nature · doi:10.1038/nature03967 · Cited by 996 · see citing works
Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner
Kalender, A., Selvaraj, A., Kim, S. Y., Gulati, P., Brûlé, S., Viollet, B., Kemp, B. E., Bardeesy, N., Dennis, P., Schlager, J. J., et al. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.03.014 · Cited by 889 · see citing works
Highly confined ions store charge more efficiently in supercapacitors
Merlet, C., Péan, C., Rotenberg, B., Madden, P. A., Daffos, B., Taberna, P., Simon, P., & Salanne, M. (2013) · Nature Communications · doi:10.1038/ncomms3701 · Cited by 746 · see citing works
Hawley, S. A., Gadalla, A. E., Olsen, G. S., & Hardie, D. G. (2002) · Diabetes · doi:10.2337/diabetes.51.8.2420 · Cited by 696 · see citing works
Harada, H., Inoue, M., Itasaka, S., Hirota, K., Morinibu, A., Shinomiya, K., Zeng, L., Ou, G., Zhu, Y., Yoshimura, M., et al. (2013) · Nature Communications · doi:10.1038/ncomms3314 · Cited by 676 · see citing works
Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade
Sanders, M. J., Grondin, P., Hegarty, B. D., Snowden, M. A., & Carling, D. (2007) · Biochemical Journal · doi:10.1042/bj20061520 · Cited by 667 · see citing works
Mammalian AMP-activated protein kinase subfamily
Stapleton, D., Mitchelhill, K. I., Gao, G., Widmer, J., Michell, B. J., Teh, T., House, C. M., Fernandez, C. S., Cox, T., Witters, L. A., et al. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.2.611 · Cited by 652 · see citing works
(1995) · FEBS Letters · doi:10.1016/0014-5793(95)01368-7 · Cited by 595 · cited 1× · see citing works
“The allosteric change leads to an increase in net phosphorylation of a subunit at T172 and AMPK activation either by augmenting phosphorylation by an upstream kinase or preventing dephosphorylation by a protein phosphatase (17).”
Structural basis for AMP binding to mammalian AMP-activated protein kinase
Xiao, B., Heath, R., Saiu, P., Leiper, F. C., Leone, P., Jing, C., Walker, P. A., Haire, L., Eccleston, J. F., Davis, C. T., et al. (2007) · Nature · doi:10.1038/nature06161 · Cited by 591 · see citing works
He, L., Sabet, A., Djedjos, S., Miller, R., Sun, X., Hussain, M. A., Radovick, S., & Wondisford, F. E. (2009) · Cell · doi:10.1016/j.cell.2009.03.016 · Cited by 479 · see citing works
The blooming of the French lilac
Witters, L. A. (2001) · Journal of Clinical Investigation · doi:10.1172/jci14178 · Cited by 370 · see citing works
Mitchelhill, K. I., Stapleton, D., Gao, G., House, C. M., Michell, B. J., Katsis, F., Witters, L. A., & Kemp, B. E. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)41951-x · Cited by 338 · see citing works
Critical phosphorylation sites for acetyl-CoA carboxylase activity.
Ha, J., Daniel, S., Broyles, S. S., & Kim, K. H. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)31770-2 · Cited by 328 · see citing works
PKA phosphorylates and inactivates AMPKα to promote efficient lipolysis
Djouder, N., Tuerk, R. D., Suter, M., Chiabotti, P. S., Thali, R. F., Scholz, R., Vaahtomeri, K., Auchli, Y., Rechsteiner, H., Brunisholz, R., et al. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.339 · Cited by 277 · see citing works
Hurley, R. L., Barré, L. K., Wood, S. D., Anderson, K. A., Kemp, B. E., Means, A. R., & Witters, L. A. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m606676200 · Cited by 264 · see citing works
AMP-activated protein kinase: Also regulated by ADP?
Hardie, D. G., Carling, D., & Gamblin, S. J. (2011) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2011.06.004 · Cited by 187 · see citing works
Dyck, J. R. B., Kudo, N., Barr, A., Davies, S. P., Hardie, D. G., & Lopaschuk, G. D. (1999) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.1999.00371.x · Cited by 175 · see citing works
DAVIES, S. P., Hawley, S. A., Woods, A., Carling, D., Haystead, T., & Hardie, D. G. (1994) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1994.tb19001.x · Cited by 173 · see citing works
Cao, J., Meng, S., Chang, E., Beckwith-Fickas, K., Xiong, L., Cole, R. N., Radovick, S., Wondisford, F. E., & He, L. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.567271 · Cited by 169 · see citing works
Cheng, J., Huang, C.-C., Liu, I.-M., Tzeng, T., & Chang, C. J. (2006) · Diabetes · doi:10.2337/diabetes.55.03.06.db05-0934 · Cited by 152 · see citing works
Stapleton, D., Gao, G., Michell, B. J., Widmer, J., Mitchelhill, K. I., Teh, T., House, C. M., Witters, L. A., & Kemp, B. E. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)43879-3 · Cited by 122 · see citing works
Ning, J., Xi, G., & Clemmons, D. R. (2011) · Endocrinology · doi:10.1210/en.2011-0155 · Cited by 112 · see citing works
Role of KLF15 in Regulation of Hepatic Gluconeogenesis and Metformin Action
Takashima, M., Ogawa, W., Hayashi, K., Inoue, H., Kinoshita, S., Okamoto, Y., Sakaue, H., Wataoka, Y., Emi, A., Senga, Y., et al. (2010) · Diabetes · doi:10.2337/db09-1679 · Cited by 112 · see citing works
Aatsinki, S., Buler, M., Salomäki, H., Koulu, M., Pavek, P., & Hakkola, J. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12585 · Cited by 85 · see citing works
Control of Foxo1 Gene Expression by Co-activator P300
Wondisford, A. R., Xiong, L., Chang, E., Meng, S., Meyers, D. J., Li, M., Cole, P. A., & He, L. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.540500 · Cited by 51 · see citing works
Transcriptional Co-activator p300 Maintains Basal Hepatic Gluconeogenesis
He, L., Naik, K., Meng, S., Cao, J., Sidhaye, A. R., Ma, A., Radovick, S., & Wondisford, F. E. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.385864 · Cited by 49 · see citing works
Kim, Y. D., Li, T., Ahn, S.-W., Kim, D., Lee, J.-M., Hwang, S., Kim, Y., Lee, C., Lee, I., Chiang, J. Y. L., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.339887 · Cited by 42 · see citing works
Activation of Basal Gluconeogenesis by Coactivator p300 Maintains Hepatic Glycogen Storage
He, L., Cao, J., Meng, S., Ma, A., Radovick, S., & Wondisford, F. E. (2013) · Molecular Endocrinology · doi:10.1210/me.2012-1413 · Cited by 29 · see citing works
Potential biomarker of metformin action
He, L., Meng, S., Germain‐Lee, E. L., Radovick, S., & Wondisford, F. E. (2014) · Journal of Endocrinology · doi:10.1530/joe-14-0084 · Cited by 23 · see citing works
Comparison of gene expression changes induced by biguanides in db/db mice liver
Heishi, M., Hayashi, K., Ichihara, J., Ishikawa, H., Kawamura, T., Kanaoka, M., Taiji, M., & Kimura, T. (2008) · The Journal of Toxicological Sciences · doi:10.2131/jts.33.339 · Cited by 15 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
“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 305 · see citing works
Wu, S., Lu, Q., Ding, Y., Wu, Y., Qiu, Y., Wang, P., Mao, X., Huang, K., Xie, Z., & Zou, M.-H. (2019) · Circulation · doi:10.1161/circulationaha.118.033552 · Cited by 298 · see citing works
Repurposing metformin: an old drug with new tricks in its binding pockets
Pryor, R., & Cabreiro, F. (2015) · Biochemical Journal · doi:10.1042/bj20150497 · Cited by 280 · see citing works
Mohammed, I., Hollenberg, M. D., Ding, H., & Triggle, C. R. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.718942 · Cited by 278 · see citing works
Metformin: Is it a drug for all reasons and diseases?
Triggle, C. R., Mohammed, I., Bshesh, K., Marei, I., Ye, K., Ding, H., MacDonald, R. S., Hollenberg, M. D., & Hill, M. A. (2022) · Metabolism · doi:10.1016/j.metabol.2022.155223 · Cited by 282 · see citing works
Metformin: A Review of Potential Mechanism and Therapeutic Utility Beyond Diabetes
Dutta, S., Shah, R., Singhal, S., Dutta, S. B., Bansal, S., Sinha, S., & Haque, M. (2023) · Drug Design Development and Therapy · doi:10.2147/dddt.s409373 · Cited by 284 · see citing works
“Meng et al, in their study on mouse-isolated hepatocytes, reported that a low concentration of metformin (25–100 μM) activated AMPK, whereas a higher concentration (500 μM) inhibited it.(51) Ravera et al studied the concentration-”
BackgroundMetformin and Systemic Metabolism
He, L. (2020) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2020.09.001 · Cited by 242 · see citing works
Autophagy in the physiological endometrium and cancer
Devis, L., Eritja, N., Davis, M. L., Matías‐Guiu, X., & Llobet‐Navàs, D. (2020) · Autophagy · doi:10.1080/15548627.2020.1752548 · Cited by 226 · see citing works
“Metformin acts through direct activation of the AMP-activated protein kinase (AMPK), and inhibition of the MTOR pathway [95,96].”
BackgroundThe mTORC1 signaling network senses changes in cellular purine nucleotide levels
Hoxhaj, G., Hughes-Hallett, J., Timson, R. C., Ilagan, E., Yuan, M., Asara, J., Ben-Sahra, I., & Manning, B. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.10.029 · Cited by 184 · see citing works
Current understanding of metformin effect on the control of hyperglycemia in diabetes
An, H., & He, L. (2016) · Journal of Endocrinology · doi:10.1530/joe-15-0447 · Cited by 202 · see citing works
“The formation of the AMPK abg heterotrimeric complex also hinders the dephosphorylation of the a1 subunit at T172 by protein phosphatase (Meng et al. 2015).”
InfluentialMetformin: A Hopeful Promise in Aging Research
Novelle, M. G., Ali, A., Diéguez, C., Bernier, M., & de Cabo, R. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a025932 · Cited by 178 · see citing works
“When therapeutic concentrations of metformin were tested, hepatic gluconeogenesis was suppressed via AMPK activation (Cao et al. 2014) and formation of AMPK abg complexes (Meng et al. 2014).”
BackgroundMetformin: An anti-diabetic drug to fight cancer
Daugan, M. V., Wojcicki, A. D., d’Hayer, B., & Boudy, V. (2016) · Pharmacological Research · doi:10.1016/j.phrs.2016.10.006 · Cited by 166 · see citing works
Johanns, M., Lai, Y., Hsu, M. F., Jacobs, R., Vertommen, D., Sande, J. V., Dumont, J. E., Woods, A., Carling, D., Hue, L., et al. (2016) · Nature Communications · doi:10.1038/ncomms10856 · Cited by 143 · see citing works
Molecular Mechanisms of Metformin for Diabetes and Cancer Treatment
Li, M., Li, X., Zhang, H., & Lü, Y. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.01039 · Cited by 121 · see citing works
“An important breakthrough was that metformin could activate adenosine 5′-monophosphate (AMP)activated protein kinase (AMPK) (Zhou et al., 2001), a master regulator of various metabolic pathways (Hardie et al., 2012; Lin and Hardie, 2018), by increasing its phosphorylation at Thr-172.”
BackgroundThe Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma
McBride, M. A., Owen, A. M., Stothers, C. L., Hernandez, A., Luan, L., Burelbach, K. R., Patil, T. K., Bohannon, J. K., Sherwood, E. R., & Patil, N. K. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01043 · Cited by 116 · see citing works
Antidiabetic Potential of Monoterpenes: A Case of Small Molecules Punching above Their Weight
Habtemariam, S. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms19010004 · Cited by 100 · see citing works
Russell, S., Lamprecht, D. A., Mandizvo, T., Jones, T., Naidoo, V., Addicott, K. W., Moodley, C., Ngcobo, B., Crossman, D. K., Wells, G., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.11.034 · Cited by 99 · see citing works
Oral delivery of metformin by chitosan nanoparticles for polycystic kidney disease
Wang, J., Chin, D. D., Poon, C. J., Mancino, V., Pham, J., Li, H., Ho, P., Hallows, K. R., & Chung, E. J. (2020) · Journal of Controlled Release · doi:10.1016/j.jconrel.2020.10.047 · Cited by 93 · see citing works
Dissecting the role of AMP-activated protein kinase in human diseases
Li, J., Zhong, L., Wang, F., & Zhu, H. (2017) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2016.12.003 · Cited by 89 · see citing works
Samuel, S., Varghese, E., Kubatka, P., Triggle, C., & Büsselberg, D. (2019) · Biomolecules · doi:10.3390/biom9120846 · Cited by 81 · see citing works
Szymczak-Pajor, I., Wenclewska, S., & Śliwińska, A. (2022) · Pharmaceuticals · doi:10.3390/ph15070810 · Cited by 81 · see citing works
“The metformin-induced AMPKαβγ complex triggers elevated phosphorylation at the Thr172 site of the α subunit via increased LKB1-dependent phosphorylation and suppression via protein phosphatase-mediated dephosphorylation [75].”
BackgroundShpakov, A. O. (2021) · Pharmaceuticals · doi:10.3390/ph14010042 · Cited by 81 · see citing works
“The MF-induced increase in the intracellular AMP level leads to the activation of AMPK as described above [41,56].”
BackgroundmTOR Inhibitors in Castration-Resistant Prostate Cancer: A Systematic Review
Statz, C. M., Patterson, S. E., & Mockus, S. M. (2016) · Targeted Oncology · doi:10.1007/s11523-016-0453-6 · Cited by 64 · see citing works
Maluf, F. C., Feder, D., & Carvalho, A. A. D. S. (2019) · Parkinson s Disease · doi:10.1155/2019/4951379 · Cited by 63 · see citing works
Pharmacology of metformin – An update
Glossmann, H. H., & Lutz, O. M. D. (2019) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2019.172782 · Cited by 61 · see citing works
Role of the AMPK/SIRT1 pathway in non‑alcoholic fatty liver disease (Review)
Anggreini, P., Kuncoro, H., Sumiwi, S. A., & Levita, J. (2022) · Molecular Medicine Reports · doi:10.3892/mmr.2022.12922 · Cited by 58 · see citing works
“AMPK Metformin Promotes the activation of AMPK by several mechanisms, (63,64)”
Catic, A. (2018) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2017.12.003 · Cited by 58 · see citing works
Metformin alleviates neurocognitive impairment in aging via activation of AMPK/BDNF/PI3K pathway
Ameen, O., Samaka, R. M., & Abo-Elsoud, R. A. A. (2022) · Scientific Reports · doi:10.1038/s41598-022-20945-7 · Cited by 55 · see citing works
Momtaz, S., Maghsoudi, A. S., Abdolghaffari, A. H., Jasemi, E., Rezazadeh, S., Hassani, S., Ziaee, M., Abdollahi, M. R., Behzad, S., & Nabavi, S. M. (2019) · Critical Reviews in Clinical Laboratory Sciences · doi:10.1080/10408363.2019.1648376 · Cited by 55 · see citing works
Counteracting Chemoresistance with Metformin in Breast Cancers: Targeting Cancer Stem Cells
Samuel, S. M., Varghese, E., Koklesová, L., Líšková, A., Kubatka, P., & Büsselberg, D. (2020) · Cancers · doi:10.3390/cancers12092482 · Cited by 53 · see citing works
“(2) Metformin selectively and preferentially targets BCSCs at lower concentrations, while a high concentration of metformin is required to effectively target terminally differentiated cancer cells [88,93].”
BackgroundWhy the endothelium? The endothelium as a target to reduce diabetes-associated vascular disease
Triggle, C. R., Ding, H., Marei, I., Anderson, T. J., & Hollenberg, M. D. (2020) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/cjpp-2019-0677 · Cited by 49 · see citing works
Yan, Y., Zhou, X. E., Novick, S. J., Shaw, S. J., Li, Y., Brunzelle, J. S., Hitoshi, Y., Griffin, P. R., Xu, H. E., & Melcher, K. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.004883 · Cited by 44 · see citing works
Zhang, L., Lu, L., Zhong, X., Yue, Y., Hong, Y., Li, Y., & Li, Y. (2019) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2019.03.006 · Cited by 44 · see citing works
Metformin Improves Metabolic Memory in High Fat Diet (HFD)-induced Renal Dysfunction
Tikoo, K., Sharma, E., Amara, V. R., Pamulapati, H., & Dhawale, V. S. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.c116.732990 · Cited by 42 · see citing works
Metformin Improves Burn Wound Healing by Modulating Microenvironmental Fibroblasts and Macrophages
Shi, L., Jiang, Z., Li, J., Lin, H., Xu, B., Liao, X., Fu, Z., Ao, H., Guo, G., & Liu, M. (2022) · Cells · doi:10.3390/cells11244094 · Cited by 41 · see citing works
“In vitro and in vivo assays have shown that metformin promotes the formation of the AMPKαβγ heterotrimeric complex, which thus activates AMPK, possibly explaining the pleiotropic effect of metformin [21].”
BackgroundActivation of the cAMP-PKA pathway Antagonizes Metformin Suppression of Hepatic Glucose Production
He, L., Chang, E., Peng, J., An, H., McMillin, S. M., Radovick, S., Stratakis, C. A., & Wondisford, F. E. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.719666 · Cited by 38 · see citing works
Samuel, S. M., Ghosh, S., Majeed, Y., Arunachalam, G., Emara, M. M., Ding, H., & Triggle, C. R. (2017) · Biochemical Pharmacology · doi:10.1016/j.bcp.2017.03.001 · Cited by 37 · see citing works
AMPK inhibits liver gluconeogenesis: fact or fiction?
Johanns, M., Hue, L., & Rider, M. H. (2023) · Biochemical Journal · doi:10.1042/bcj20220582 · Cited by 42 · see citing works
Weiss, R., Fernández, E., Liu, Y., Strong, R., & Salmon, A. B. (2018) · Aging · doi:10.18632/aging.101401 · Cited by 36 · see citing works
“The mechanism of action for metformin is still controversial and metformin has been proposed to stimulate the AMP-activated protein kinase (AMPK) pathway by inhibiting complex I activity in the mitochondria [26, 27], by inhibition of mitochondrial redox shuttle enzymes [28] or through mitochondria independent mechanis…”
BackgroundRole of Phosphodiesterase in the Biology and Pathology of Diabetes
Kilanowska, A., & Ziółkowska, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218244 · Cited by 34 · see citing works
Mitochondria-associated endoplasmic reticulum membranes in the heart
Wu, S., & Zou, M. (2018) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2018.12.018 · Cited by 32 · see citing works
PPP1R3C mediates metformin-inhibited hepatic gluconeogenesis
Ji, X., Wang, S., Tang, H., Zhang, Y., Zhou, F., Zhang, L., Zhu, Q., Zhu, K., Liu, Q., Liu, Y., et al. (2019) · Metabolism · doi:10.1016/j.metabol.2019.06.002 · Cited by 31 · see citing works
Al-Kuraishy, H. M., & Al-Gareeb, A. I. (2015) · Emergency Medicine International · doi:10.1155/2015/283021 · Cited by 29 · see citing works
Venu, V. K. P., Saifeddine, M., Mihara, K., Faiza, M., Gorobets, E., Flewelling, A. J., Derksen, D. J., Hirota, S. A., Marei, I., Al-Majid, D., et al. (2021) · Molecular Pharmacology · doi:10.1124/molpharm.120.000148 · Cited by 29 · see citing works
Al‐Oanzi, Z. H., Fountana, S., Moonira, T., Tudhope, S. J., Petrie, J. L., Alshawi, A., Patman, G., Arden, C., Reeves, H. L., & Agius, L. (2017) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12910 · Cited by 28 · see citing works
“Despite clear evidence for AMPK activation by metformin [4], also at low concentrations [46] there remain cogent arguments for AMPK-independent mechanisms [3,5].”
BackgroundSung, J. Y., Kim, S. G., Kang, Y. J., & Choi, H. C. (2022) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2022.111708 · Cited by 28 · see citing works
Yibcharoenporn, C., Muanprasat, C., Moonwiriyakit, A., Satitsri, S., & Pathomthongtaweechai, N. (2025) · Drug Design Development and Therapy · doi:10.2147/dddt.s507489 · Cited by 25 · see citing works
Mroueh, F. M., Noureldein, M. H., Zeidan, Y. H., Boutary, S. S., Irani, S. A. M., Eid, S., Haddad, M. E., Barakat, R., Harb, F., Costantine, J., et al. (2019) · The FASEB Journal · doi:10.1096/fj.201900396rr · Cited by 26 · see citing works
An Overview of Autophagy in Helicobacter pylori Infection and Related Gastric Cancer
Yang, Y., Shu, X., & Xie, C. (2022) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2022.847716 · Cited by 26 · see citing works
Luo, Z., Zhu, T., Luo, W., Lv, Y., Zhang, L., Wang, C., Li, M., Wu, W., & Shi, S. (2019) · Cancer Management and Research · doi:10.2147/cmar.s178688 · Cited by 26 · see citing works
“Shumei Meng and Jia Cao have reported that low concentrations of metformin suppress glucose production by activating AMPK.(37,38) AMPK is downregulated in hepatocellular carcinoma, low p-AMPK expression is associated with poor prognosis, and metformin inhibits hepatocellular carcinoma by inducing AMPK activation.”
BackgroundPhenformin and metformin inhibit growth and migration of LN229 glioma cells in vitro and in vivo
Wang, Y., Meng, Y., Zhang, S., Wu, H., Yang, D., Nie, C., & Hu, Q. (2018) · OncoTargets and Therapy · doi:10.2147/ott.s168981 · Cited by 25 · see citing works
The importance of the AMPK gamma 1 subunit in metformin suppression of liver glucose production
An, H., Wang, Y., Qin, C., Li, M., Maheshwari, A., & He, L. (2020) · Scientific Reports · doi:10.1038/s41598-020-67030-5 · Cited by 25 · see citing works
Metformin ameliorates the severity of experimental Alport syndrome
Omachi, K., Kaseda, S., Yokota, T., Kamura, M., Teramoto, K., Kuwazuru, J., Kojima, H., Nohara, H., Koyama, K., Ohtsuki, S., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-86109-1 · Cited by 26 · see citing works
Metformin and Glaucoma—Review of Anti-Fibrotic Processes and Bioenergetics
Hurley, D. J., Irnaten, M., & O'Brien, C. J. (2021) · Cells · doi:10.3390/cells10082131 · Cited by 24 · see citing works
Mao, Y., Ren, J. T., & Yang, L. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.887045 · Cited by 24 · see citing works
“In line with this finding, results from the British Prospective Diabetes Study suggested that metformin, one common antidiabetic drugs for type 2 diabetes and AMPK activator (Zhou et al., 2001; Xie et al., 2008; Xie et al., 2011; Meng et al., 2015), improved cardiac function and reduced incidence of myocardial infarct…”
BackgroundResultDong, Y. J., Chen, Y.-T., Yang, Y., Shou, D., & Li, C. (2016) · Molecules · doi:10.3390/molecules21111446 · Cited by 24 · see citing works
“Much more recent studies have suggested that metformin could activate AMP-activated protein kinase (AMPK) by causing decreases in hepatic energy charge (increasing AMP:ADP or ADP:ATP concentration ratios, or both) and could suppress gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase [11,12].”
BackgroundMetformin prevents ischaemic ventricular fibrillation in metabolically normal pigs
Lu, L., Ye, S., Scalzo, R. L., Reusch, J. E. B., Greyson, C. R., & Schwartz, G. G. (2017) · Diabetologia · doi:10.1007/s00125-017-4287-2 · Cited by 23 · see citing works
“AMPK, p-AMPK-Thr(172) and CS activity A biochemical signature of metformin action in target tissues is activation of AMPK as indicated by its phosphorylation at Thr(172) (p-AMPK) [24].”
BackgroundAcı́n, S., Muñoz, D. L., Guillén, A., Soscue, D., Castaño, A., Echeverri, F., & Balcázar, N. (2020) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2020.113298 · Cited by 22 · see citing works
The role of PP5 and PP2C in cardiac health and disease
Neumann, J., Boknı́k, P., Kirchhefer, U., & Gergs, U. (2021) · Cellular Signalling · doi:10.1016/j.cellsig.2021.110035 · Cited by 22 · see citing works
Teng, X., Brown, J., & Morel, L. M. (2021) · Antioxidants and Redox Signaling · doi:10.1089/ars.2021.0070 · Cited by 21 · see citing works
“Metformin can also increase AMP levels independently from OXPHOS by deac-tivating AMP deaminase (94), and it directly activates AMPK by promoting the formation of its trimeric complex (82).”
The gastrointestinal tract is a major source of the acute metformin-stimulated rise in GDF15
Kincaid, J. W. R., Rimmington, D., Tadross, J. A., Cimino, I., Zvetkova, I., Kaser, A., Richards, P., Patel, S., O’Rahilly, S., & Coll, A. P. (2024) · Scientific Reports · doi:10.1038/s41598-024-51866-2 · Cited by 19 · see citing works
Acosta, M. A. T., Gurkan, J. K., Liu, Q., Mambetsariev, N., Liu, Q., Helmin, K. A., Joudi, A. M., Morales‐Nebreda, L., Cheng, K., Abdala‐Valencia, H., et al. (2025) · Journal of Clinical Investigation · doi:10.1172/jci179572 · Cited by 23 · see citing works
“Clinical trial data suggest that metformin, an indirect AMPK activator, significantly reduces the risk of developing long COVID (53–55).”
Autophagy in adult stem cell homeostasis, aging, and disease therapy
Zhao, K., Chan, I. T. C., Tse, E. H. Y., Xie, Z., Cheung, T. H., & Zeng, Y. A. (2025) · Cell Regeneration · doi:10.1186/s13619-025-00224-2 · Cited by 22 · see citing works
Uddin, J., Sharma, A., Wu, D. X.-Y., Tomar, S., Ganesan, V., Reichel, P. E., Thota, L. N., Cabrera-Silva, R. I., Marella, S., Idelman, G., et al. (2024) · JCI Insight · doi:10.1172/jci.insight.172978 · Cited by 19 · see citing works
“Metformin has pleiotropic actions and can act via AMPK-dependent and -independent mechanisms.”
InfluentialRajh, M., Dolinar, K., Miš, K., Pavlin, M., & Pirkmajer, S. (2016) · PLoS ONE · doi:10.1371/journal.pone.0154747 · Cited by 20 · see citing works
“Metformin can activate AMPK also by inhibiting AMP deamination [15] or by promoting formation of the functional AMPK heterotrimeric complexes [16].”
BackgroundGrycel, S., Markowski, A. R., Hady, H. R., Zabielski, P., Kojta, I., Imierska, M., Górski, J., & Błachnio-Zabielska, A. U. (2019) · Nutrition · doi:10.1016/j.nut.2019.01.019 · Cited by 18 · see citing works
Yan, X., Yang, Y., Huang, W., Fu, S.-P., Cui, B., Chu, M., Yang, D., Peng, Y., Song, H., Shi, J., et al. (2025) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2025.119425 · Cited by 17 · see citing works
Targeting Lipophagy in Liver Diseases: Impact on Oxidative Stress and Steatohepatitis
Hwang, J. S., Lai, T. H., & Kim, D. R. (2025) · Antioxidants · doi:10.3390/antiox14080908 · Cited by 18 · see citing works
“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].”
Zou, H., Zou, H., Li, X., Qiu, Q., Geng, N., Zhang, B.-H., Yan, G., Zhang, Z., Zhang, S., Yao, B., et al. (2022) · Pesticide Biochemistry and Physiology · doi:10.1016/j.pestbp.2022.105083 · Cited by 17 · see citing works
Pearah, A., Ramatchandirin, B., Liu, T., Wolf, R. M., Ikeda, A., Radovick, S., Sesaki, H., Wondisford, F. E., O'Rourke, B. P., & He, L. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2023.09.017 · Cited by 17 · see citing works
Zhang, M., Fang, X.-S., Guo, J., & Jin, Z. (2019) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-019-00870-9 · Cited by 17 · see citing works
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 · see citing works
“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).”
BackgroundZhang, J., Hang, C., Jiang, T., Yi, S., Shao, W., Li, W., & Lin, D. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.570516 · Cited by 16 · see citing works
Shoaib, M., Choudhary, R. C., Kumar, R., Kim, N., Miyara, S. J., Haque, S., Yin, T., Frankfurt, M., Molmenti, E. P., Zanos, S. P., et al. (2022) · The FASEB Journal · doi:10.1096/fj.202200121r · Cited by 16 · see citing works
Bikas, A., Nostrand, D. V., Jensen, K. E., Desale, S. Y., Mete, M., Patel, A. D., Wartofsky, L., Vasko, V. V., & Burman, K. D. (2015) · Thyroid · doi:10.1089/thy.2015.0413 · Cited by 16 · see citing works
Bioactive compounds, pharmacological actions and pharmacokinetics of Cupressus sempervirens
Batiha, G. E., Teibo, J. O., Shaheen, H. M., Akinfe, O. A., Awad, A. A., Teibo, T. K. A., Alexiou, A. T., & Papadakis, M. (2022) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-022-02326-z · Cited by 14 · see citing works
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 14 · see citing works
Metformin Effects on SHIP2, AMPKs and Gut Microbiota: Recent Updates on Pharmacology
Shivaprakash, P., Beeraka, N. M., Madhunapantula, S. V., Nikolenko, V. N., & Basalingappa, K. M. (2024) · Current Medicinal Chemistry · doi:10.2174/0109298673289342240213040144 · Cited by 13 · see citing works
Metformin improves Mycobacterium avium infection by strengthening macrophage antimicrobial functions
Mediaas, S. D., Haug, M., Louet, C., Wahl, S. G. F., Gidon, A., & Flo, T. H. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1463224 · Cited by 13 · see citing works
Skórzyńska-Dziduszko, K., Kimber-Trojnar, Ż., Patro-Małysza, J., Stenzel-Bembenek, A., Oleszczuk, J., & Leszczyńska‐Gorzelak, B. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19103205 · Cited by 12 · see citing works
“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].”
BackgroundRada, P., Mosquera, A., Muntané, J., Ferrándiz, F., Rodríguez‐Mañas, L., de Pablo, F., González‐Canudas, J., & Valverde, Á. M. (2018) · Food and Chemical Toxicology · doi:10.1016/j.fct.2018.11.019 · Cited by 12 · see citing works
“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 15 · see citing works
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 · see citing works
“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
Lushchak, O. V., Gospodaryov, D. V., Strilbytska, O. M., & Bayliak, M. M. (2023) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2023.03.005 · Cited by 11 · see citing works
Hwang, S., Choi, Y., Wang, J., & Son, C. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116250 · Cited by 11 · see citing works
Mechanisms of Action of Metformin
Mahmood, S. A. (2021) · IntechOpen eBooks · doi:10.5772/intechopen.99189 · Cited by 10 · see citing works
Rezaei, S., Timani, K. A., & He, J. J. (2023) · Aging and Disease · doi:10.14336/ad.2023.0705 · Cited by 10 · see citing works
Therapeutically relevant natural products as AMPK activators in the treatment of diabetes
Germán-Acacio, J. M., Meza-Sánchez, D. E., & Morales‐Morales, D. (2020) · Studies in natural products chemistry · doi:10.1016/b978-0-12-817907-9.00003-9 · Cited by 9 · see citing works
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 9 · see citing works
Gutierrez-Lara, E. J., Martínez-Conde, C., Rosales-Ortega, E., Ramírez‐Espinosa, J. J., Rivera‐Leyva, J. C., Centurión, D., Carvajal, K., Ortega-Cuéllar, D., Estrada-Soto, S. E., & Navarrete‐Vázquez, G. (2017) · Journal of Chemistry · doi:10.1155/2017/1212609 · Cited by 9 · see citing works
“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 · see citing works
Chen, M., Li, F., Qu, M., Jin, X., He, T., He, S., Chen, S., Yao, Q., Wang, L., Chen, D., et al. (2024) · Aging Cell · doi:10.1111/acel.14237 · Cited by 8 · see citing works
Trisal, A., & Singh, A. K. (2025) · Neuroscience · doi:10.1016/j.neuroscience.2025.01.004 · Cited by 8 · see citing works
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 · see citing works
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 · see citing works
Pușcașu, C., Ungurianu, A., Șeremet, O. C., Andrei, C., Mihai, D. P., & Negreș, S. (2023) · Medicina · doi:10.3390/medicina59081375 · Cited by 8 · see citing works
“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
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
