Metformin Inhibits Hepatic Gluconeogenesis in Mice Independently of the LKB1/AMPK Pathway via a Decrease in Hepatic Energy State
Open accessAbstract
Metformin is widely used to treat hyperglycemia in individuals with type 2 diabetes. Recently the LKB1/AMP-activated protein kinase (LKB1/AMPK) pathway was proposed to mediate the action of metformin on hepatic gluconeogenesis. However, the molecular mechanism by which this pathway operates had remained elusive. Surprisingly, here we have found that in mice lacking AMPK in the liver, blood glucose levels were comparable to those in wild-type mice, and the hypoglycemic effect of metformin was maintained. Hepatocytes lacking AMPK displayed normal glucose production and gluconeogenic gene expression compared with wild-type hepatocytes. In contrast, gluconeogenesis was upregulated in LKB1-deficient hepatocytes. Metformin decreased expression of the gene encoding the catalytic subunit of glucose-6-phosphatase (G6Pase), while cytosolic phosphoenolpyruvate carboxykinase (Pepck) gene expression was unaffected in wild-type, AMPK-deficient, and LKB1-deficient hepatocytes. Surprisingly, metformin-induced inhibition of glucose production was amplified in both AMPK- and LKB1-deficient compared with wild-type hepatocytes. This inhibition correlated in a dose-dependent manner with a reduction in intracellular ATP content, which is crucial for glucose production. Moreover, metformin-induced inhibition of glucose production was preserved under forced expression of gluconeogenic genes through PPARgamma coactivator 1alpha (PGC-1alpha) overexpression, indicating that metformin suppresses gluconeogenesis via a transcription-independent process. In conclusion, we demonstrate that metformin inhibits hepatic gluconeogenesis in an LKB1- and AMPK-independent manner via a decrease in hepatic energy state.
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?
Studies have reported AMPK/LKB1 independent effects of metformin on gluconeogenesis.
“studies have also reported AMPK/LKB1 independent effects of metformin on gluconeogenesis (135).”
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 [135]
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
HIGH-YIELD PREPARATION OF ISOLATED RAT LIVER PARENCHYMAL CELLS
Berry, M. N., & Friend, D. S. (1969) · The Journal of Cell Biology · doi:10.1083/jcb.43.3.506 · Cited by 4,407 · see citing works
Resveratrol improves health and survival of mice on a high-calorie diet
Baur, J. A., Pearson, K. J., Price, N. L., Jamieson, H. A., Lerin, C., Kalra, A., Prabhu, V. V., Allard, J. S., Lopez-Lluch, G., Lewis, K., et al. (2006) · Nature · doi:10.1038/nature05354 · Cited by 4,290 · see citing works
A simplified system for generating recombinant adenoviruses
He, T., Zhou, S., da Costa, L. T., Yu, J., Kinzler, K. W., & Vogelstein, B. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.5.2509 · Cited by 3,209 · 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
Shaw, R. J., Kosmatka, M., Bardeesy, N., Hurley, R. L., Witters, L. A., DePinho, R. A., & Cantley, L. C. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308061100 · Cited by 1,797 · see citing works
Bailey, C. J., & Turner, R. C. (1996) · New England Journal of Medicine · doi:10.1056/nejm199602293340906 · Cited by 1,726 · see citing works
Hawley, S. A., Boudeau, J., Reid, J. L., Mustard, K. J., Udd, L., Mäkelä, T. P., Alessi, D. R., & Hardie, D. G. (2003) · Journal of Biology · doi:10.1186/1475-4924-2-28 · Cited by 1,666 · 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
Hawley, S. A., Pan, D. A., Mustard, K. J., Ross, L., Bain, J., Edelman, A. M., Frenguelli, B. G., & Hardie, D. G. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.05.009 · Cited by 1,589 · 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
Woods, A., Dickerson, K., Heath, R. B., Hong, S. P., Momcilovic, M., Johnstone, S. R., Carlson, M., & Carling, D. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.06.005 · Cited by 1,382 · 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
Corton, J. M., Gillespie, J. G., Hawley, S. A., & Hardie, D. G. (1995) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1995.tb20498.x · Cited by 1,232 · see citing works
Kirpichnikov, D., McFarlane, S. I., & Sowers, J. R. (2002) · Annals of Internal Medicine · doi:10.7326/0003-4819-137-1-200207020-00009 · Cited by 1,084 · 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
Zong, H., Ren, J. M., Young, L. H., Pypaert, M., Mu, J., Birnbaum, M. J., & Shulman, G. I. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.252625599 · Cited by 1,036 · 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 993 · see citing works
Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action
Shu, Y., Sheardown, S. A., Brown, C., Owen, R., Zhang, S., Castro, R. A., Ianculescu, A. G., Lin, Y., Lo, J. C.-M., Burchard, E. G., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30558 · Cited by 963 · see citing works
Cool, B. L., Zinker, B. A., Chiou, W. J. H., Kifle, L., Cao, N., Perham, M., Dickinson, R., Adler, A. L., Gagné, G. D., Iyengar, R., et al. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.05.005 · Cited by 932 · see citing works
Adenosine Triphosphate Conservation in Metabolic Regulation
Atkinson, D., & Walton, G. M. (1967) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)95956-9 · Cited by 910 · see citing works
Musi, N., Hirshman, M. F., Nygren, J., Svanfeldt, M., Bavenholm, P., Rooyackers, O., Zhou, G., Williamson, J. M., Ljunqvist, O., Efendic, S., et al. (2002) · Diabetes · doi:10.2337/diabetes.51.7.2074 · Cited by 806 · see citing works
Foretz, M., Guichard, C., Ferré, P., & Foufelle, F. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.22.12737 · Cited by 748 · see citing works
Self-citationMetformin reverses fatty liver disease in obese, leptin-deficient mice.
Lin, H. Z., Yang, S. Q., Chuckaree, C., Kuhajda, F., Ronnet, G., & Diehl, A. M. (2000) · Nature Medicine · doi:10.1038/79697 · Cited by 673 · 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 660 · see citing works
Apc Tumor Suppressor Gene Is the “Zonation-Keeper” of Mouse Liver
Benhamouche, S., Decaens, T., Godard, C., Chambrey, R., Rickman, D. S., Moinard, C., Vasseur-Cognet, M., Kuo, C. J., Kahn, A., Perret, C., et al. (2006) · Developmental Cell · doi:10.1016/j.devcel.2006.03.015 · Cited by 543 · see citing works
Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction
Sakamoto, K., McCarthy, A., Smith, D. P., Green, K. A., Hardie, D. G., Ashworth, A., & Alessi, D. R. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600667 · Cited by 538 · see citing works
Self-citationTurner, N., Li, J.-Y., Gosby, A., To, S. W. C., Cheng, Z., Miyoshi, H., Taketo, M. M., Cooney, G. J., Kraegen, E. W., James, D. E., et al. (2008) · Diabetes · doi:10.2337/db07-1552 · Cited by 535 · see citing works
Viollet, B., Foretz, M., Guigas, B., Horman, S., Dentin, R., Bertrand, L., Hue, L., & Andréelli, F. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.108506 · Cited by 529 · see citing works
Self-citationThe AMP-activated protein kinase α2 catalytic subunit controls whole-body insulin sensitivity
Viollet, B., Andreelli, F., Jørgensen, S. B., Perrin, C., Geloen, A., Flamez, D., Mu, J., Lenzner, C., Baud, O., Bennoun, M., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci16567 · Cited by 499 · see citing works
Self-citationViollet, B., Guigas, B., Leclerc, J., Hébrard, S., Lantier, L., Mounier, R., Andréelli, F., & Foretz, M. (2009) · Acta Physiologica · doi:10.1111/j.1748-1716.2009.01970.x · Cited by 486 · see citing works
Self-citationHe, 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
Zang, M., Zuccollo, A., Hou, X., Nagata, D., Walsh, K. X., Herscovitz, H., Brecher, P. I., Ruderman, N. B., & Cohen, R. A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m408149200 · Cited by 450 · see citing works
Mechanism of Action of A-769662, a Valuable Tool for Activation of AMP-activated Protein Kinase
Göransson, O., McBride, A., Hawley, S. A., Ross, F. A., Shpiro, N., Foretz, M., Viollet, B., Hardie, D. G., & Sakamoto, K. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m706536200 · Cited by 433 · see citing works
Self-citationAccumulation of Metformin by Tissues of the Normal and Diabetic Mouse
Wilcock, C., & Bailey, C. J. (1994) · Xenobiotica · doi:10.3109/00498259409043220 · Cited by 418 · see citing works
AMP-Activated Protein Kinase as a Drug Target
Hardie, D. G. (2006) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.47.120505.105304 · Cited by 405 · see citing works
Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2
Dentin, R., Liu, Y., Koo, S., Hedrick, S. A., Vargas, T., Heredia, J., Yates, J. R., & Montminy, M. (2007) · Nature · doi:10.1038/nature06128 · Cited by 400 · see citing works
Sakamoto, K., Göransson, O., Hardie, D. G., & Alessi, D. R. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00074.2004 · Cited by 299 · see citing works
Role of AMP-activated Protein Kinase in Cyclic AMP-dependent Lipolysis In 3T3-L1 Adipocytes
Wu, Y., Mu, J., & Birnbaum, M. J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m308484200 · Cited by 287 · see citing works
The prevention of type 2 diabetes
F. T. D. P. P. R. G., Crandall, J. P., Knowler, W. C., Kahn, S. E., Marrero, D., Florez, J. C., Bray, G. A., Haffner, S. M., Hoskin, M., & Nathan, D. M. (2008) · Nature Clinical Practice Endocrinology & Metabolism · doi:10.1038/ncpendmet0843 · Cited by 261 · see citing works
Foretz, M., Carling, D., Guichard, C., Ferré, P., & Foufelle, F. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.24.14767 · Cited by 256 · see citing works
Self-citationScott, J. W., van Denderen, B. J. W., Jørgensen, S. B., Honeyman, J. E., Steinberg, G. R., Oakhill, J. S., Iseli, T. J., Koay, A. Z., Gooley, P. R., Stapleton, D., et al. (2008) · Chemistry & Biology · doi:10.1016/j.chembiol.2008.10.005 · Cited by 252 · see citing works
Cellular Mechanism of Action of Metformin
Klip, A., & Leiter, L. A. (1990) · Diabetes Care · doi:10.2337/diacare.13.6.696 · Cited by 238 · see citing works
Deficiency of LKB1 in heart prevents ischemia-mediated activation of AMPKα2 but not AMPKα1
Sakamoto, K., Zarrinpashneh, E., Budas, G. R., Pouleur, A., Dutta, A., Prescott, A. R., Vanoverschelde, J., Ashworth, A., Jovanović, A., Alessi, D. R., et al. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00443.2005 · Cited by 221 · see citing works
Self-citationInhibition by AICA Riboside of Gluconeogenesis in Isolated Rat Hepatocytes
Vincent, M., Marangos, P. J., Gruber, H. E., & Berghe, G. (1991) · Diabetes · doi:10.2337/diab.40.10.1259 · Cited by 218 · see citing works
Horike, N., Sakoda, H., Kushiyama, A., Ono, H., Fujishiro, M., Kamata, H., Nishiyama, K., Uchijima, Y., Kurihara, Y., Kurihara, H., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m802537200 · Cited by 192 · see citing works
Guigas, B., Bertrand, L., Taleux, N., Foretz, M., Wiernsperger, N. F., Vertommen, D., Andréelli, F., Viollet, B., & Hue, L. (2006) · Diabetes · doi:10.2337/diabetes.55.04.06.db05-1178 · Cited by 181 · see citing works
Self-citationArgaud, D., Roth, H., Wiernsperger, N. F., & Leverve, X. M. (1993) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1993.tb17886.x · Cited by 151 · see citing works
Guigas, B., Taleux, N., Foretz, M., Détaille, D., Andréelli, F., Viollet, B., & Hue, L. (2007) · Biochemical Journal · doi:10.1042/bj20070105 · Cited by 117 · see citing works
Self-citationGlucose controls CREB activity in islet cells via regulated phosphorylation of TORC2
Jansson, D., Ng, A. C.-H., Fu, A., Depatie, C., Azzabi, M. A., & Screaton, R. A. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0800796105 · Cited by 115 · see citing works
Burgess, S. C., Leone, T. C., Wende, A. R., Croce, M. A., Chen, Z., Sherry, A. D., Malloy, C. R., & Finck, B. N. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m600050200 · Cited by 111 · see citing works
The Effect of Intravenous Metformin on Glucose Metabolism During Hyperglycaemia in Type 2 Diabetes
Sum, C. ‐., Webster, J. M., Johnson, A. B., Catalano, C., Cooper, B. G., & Taylor, R. (1992) · Diabetic Medicine · doi:10.1111/j.1464-5491.1992.tb01716.x · Cited by 103 · see citing works
Mithieux, G., Guignot, L., Bordet, J., & Wiernsperger, N. F. (2002) · Diabetes · doi:10.2337/diabetes.51.1.139 · Cited by 103 · see citing works
Self-citationBryła, J., Harris, E. J., & Plumb, J. A. (1977) · FEBS Letters · doi:10.1016/0014-5793(77)80494-8 · Cited by 94 · see citing works
Beyond AICA riboside: In search of new specific AMP‐activated protein kinase activators
Guigas, B., Sakamoto, K., Taleux, N., Reyna, S. M., Musi, N., Viollet, B., & Hue, L. (2009) · IUBMB Life · doi:10.1002/iub.135 · Cited by 86 · see citing works
Self-citationSubcellular Distribution of Metformin in Rat Liver
Wilcock, C., Wyre, N. D., & Bailey, C. J. (1991) · Journal of Pharmacy and Pharmacology · doi:10.1111/j.2042-7158.1991.tb03507.x · Cited by 86 · see citing works
Sites of metformin-stimulated glucose metabolism
Wilcock, C., & Bailey, C. J. (1990) · Biochemical Pharmacology · doi:10.1016/0006-2952(90)90136-9 · Cited by 67 · see citing works
Pryor, H. J., SMYTH, J. E., Quinlan, P. T., & Halestrap, A. P. (1987) · Biochemical Journal · doi:10.1042/bj2470449 · Cited by 56 · see citing works
Bandsma, R., van Dijk, T. H., ter Harmsel, A., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m310067200 · Cited by 54 · see citing works
Qiu, B., Turner, N. A., Li, Y., Gu, M., Huang, M., Wu, F., Pang, T., Nan, F., Ye, J., Li, J.-Y., et al. (2009) · Diabetes · doi:10.2337/db09-0223 · Cited by 50 · see citing works
Metformin beyond diabetes: new life for an old drug.
Rotella, C., Monami, M., & Mannucci, E. (2006) · Current Diabetes Reviews · doi:10.2174/157339906777950651 · Cited by 50 · see citing works
Raso, G. M., Esposito, E., Iacono, A., Pacilio, M., Cuzzocrea, S., Canani, R. B., Calignano, A., & Meli, R. (2008) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2008.12.013 · Cited by 41 · see citing works
The mechanisms by which mild respiratory chain inhibitors inhibit hepatic gluconeogenesis
Owen, M. R., & Halestrap, A. P. (1993) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/0005-2728(93)90079-u · Cited by 41 · see citing works
Mukhtar, M. H., Payne, V. A., Arden, C., Harbottle, A., Khan, S. A., Lange, A. J., & Agius, L. (2008) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00593.2007 · Cited by 38 · see citing works
Rajas, F., Jourdan‐Pineau, H., Stefanutti, A., Mrad, E. A., Iynedjian, P. B., & Mithieux, G. (2007) · Histochemistry and Cell Biology · doi:10.1007/s00418-006-0263-5 · Cited by 37 · see citing works
Self-citationInhibition by AICA riboside of gluconeogenesis in isolated rat hepatocytes
Vincent, M. F., Marangos, P. J., Gruber, H. E., et al. (1991) · Diabetes · doi:10.2337/diabetes.40.10.1259 · Cited by 37 · see citing works
Coronary Surgery in a Patient Receiving Hemodialysis
North, R. L. (1977) · Archives of Internal Medicine · doi:10.1001/archinte.1977.03630130011003 · Cited by 7 · see citing works
Coronary surgery in a patient receiving hemodialysis
North, R. L. (1977) · Archives of Internal Medicine · doi:10.1001/archinte.137.1.25 · Cited by 1 · see citing works
Flagged first, then by citations
Research works printed but not linked: 3
- Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334(9):574-579.
- Kirpichnikov D, McFarlane SI, Sowers JR. Metfor- min: an update. Ann Intern Med. 2002;137(1):25-33.
- Sakamoto K, et al. Deficiency of LKB1 in heart pre- vents ischemia-mediated activation of AMPKal- pha2 but not AMPKalpha1. Am J Physiol Endocrinol Metab. 2006;290(5):E780-E788.
Cited by
Sorted by citations
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
The AMPK signalling pathway coordinates cell growth, autophagy and metabolism
Mihaylova, M. M., & Shaw, R. J. (2011) · Nature Cell Biology · doi:10.1038/ncb2329 · Cited by 2,923 · see citing works
The mechanisms of action of metformin
Rena, G., Hardie, D. G., & Pearson, E. R. (2017) · Diabetologia · doi:10.1007/s00125-017-4342-z · Cited by 2,287 · see citing works
Cellular and molecular mechanisms of metformin: an overview
Viollet, B., Guigas, B., Garcia, N. S., Leclerc, J., Foretz, M., & Andreelli, F. (2012) · Clinical Science · doi:10.1042/cs20110386 · Cited by 1,720 · see citing works
Self-citationAMP-activated protein kinase: an energy sensor that regulates all aspects of cell function
Hardie, D. G. (2011) · Genes & Development · doi:10.1101/gad.17420111 · Cited by 1,638 · see citing works
Wu, H., Esteve, E., Tremaroli, V., Khan, M. T., Caesar, R., Mannerås-Holm, L., Ståhlman, M., Olsson, L. M., Serino, M., Planas-Fèlix, M., et al. (2017) · Nature Medicine · doi:10.1038/nm.4345 · Cited by 1,632 · see citing works
Metformin: from mechanisms of action to therapies
Foretz, M., Guigas, B., Bertrand, L., Pollak, M., & Viollet, B. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.09.018 · Cited by 1,501 · see citing works
Self-citationKinaan, M., Ding, H., & Triggle, C. R. (2015) · Medical Principles and Practice · doi:10.1159/000381643 · Cited by 1,515 · see citing works
Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase
Madiraju, A. K., Erion, D. M., Rahimi, Y., Zhang, X.-M., Braddock, D. T., Albright, R. A., Prigaro, B. J., Wood, J. L., Bhanot, S., MacDonald, M. J., et al. (2014) · Nature · doi:10.1038/nature13270 · Cited by 1,284 · see citing works
Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis
Wheaton, W. W., Weinberg, S. E., Hamanaka, R. B., Soberanes, S., Sullivan, L. B., Anso, E., Glasauer, A., Dufour, E., Mutlu, G. M., Budigner, G. S., et al. (2014) · eLife · doi:10.7554/elife.02242 · Cited by 1,105 · see citing works
Metformin as a tool to target aging
Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.05.011 · Cited by 1,096 · see citing works
Fullerton, M. D., Galic, S., Marcinko, K., Sikkema, S., Pulinilkunnil, T., Chen, Z.-P., O'Neill, H. M., Ford, R. J., Palanivel, R., O'Brien, M., et al. (2013) · Nature Medicine · doi:10.1038/nm.3372 · Cited by 893 · see citing works
AMPK activators: mechanisms of action and physiological activities
Kim, J., Yang, G., Kim, Y., Kim, J., & Ha, J. (2016) · Experimental & Molecular Medicine · doi:10.1038/emm.2016.16 · Cited by 817 · see citing works
Obesity and diabetes: the increased risk of cancer and cancer-related mortality
Gallagher, E. J., & LeRoith, D. (2015) · Physiological Reviews · doi:10.1152/physrev.00030.2014 · Cited by 806 · see citing works
Cellular and Molecular Mechanisms of Metformin Action
LaMoia, T. E., & Shulman, G. I. (2021) · Endocrine Reviews · doi:10.1210/endrev/bnaa023 · Cited by 791 · see citing works
Benefits of Metformin in Attenuating the Hallmarks of Aging
Kulkarni, A. S., Gubbi, S., & Barzilai, N. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.04.001 · Cited by 766 · see citing works
Anti-inflammatory effects of metformin irrespective of diabetes status
Cameron, A. R., Morrison, V. L., Levin, D., Mohan, M., Forteath, C., Beall, C., McNeilly, A. D., Balfour, D. J. K., Savinko, T., Wong, A. K. F., et al. (2016) · Circulation Research · doi:10.1161/circresaha.116.308445 · Cited by 704 · see citing works
Self-citationUnderstanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus
Foretz, M., Guigas, B., & Viollet, B. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0242-2 · Cited by 686 · see citing works
Self-citationLow-dose metformin targets the lysosomal AMPK pathway through PEN2
Ma, T., Tian, X., Zhang, B., Li, M., Wang, Y., Yang, C., Wu, J., Wei, X., Qu, Q., Yu, Y., et al. (2022) · Nature · doi:10.1038/s41586-022-04431-8 · Cited by 644 · see citing works
The role of mitochondria in insulin resistance and type 2 diabetes mellitus
Szendroedi, J., Phielix, E., & Roden, M. (2012) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2011.138 · Cited by 600 · see citing works
Shackelford, D. B., Abt, E., Gerken, L., Vasquez, D. S., Seki, A., Leblanc, M., Wei, L., Fishbein, M. C., Czernin, J., Mischel, P. S., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2012.12.008 · Cited by 585 · see citing works
Gowans, G. J., Hawley, S. A., Ross, F. A., & Hardie, D. G. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.08.019 · Cited by 531 · see citing works
AMPK at the Nexus of Energetics and Aging
Burkewitz, K., Zhang, Y., & Mair, W. B. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.03.002 · Cited by 483 · see citing works
Metformin pathways: pharmacokinetics and pharmacodynamics
Gong, L., Goswami, S., Giacomini, K. M., Altman, R. B., & Klein, T. E. (2012) · Pharmacogenetics and Genomics · doi:10.1097/fpc.0b013e3283559b22 · Cited by 495 · see citing works
From pre-diabetes to diabetes: diagnosis, treatments and translational research
Khan, R., Chua, Z., Tan, J., Yang, Y., Liao, Z., & Zhao, Y. (2019) · Medicina · doi:10.3390/medicina55090546 · Cited by 484 · see citing works
Molecular mechanism of action of metformin: old or new insights?
Rena, G., Pearson, E. R., & Sakamoto, K. (2013) · Diabetologia · doi:10.1007/s00125-013-2991-0 · Cited by 479 · see citing works
Self-citationMetformin and inflammation: its potential Beyond glucose-lowering effect
Saisho, Y. (2015) · Endocrine, Metabolic & Immune Disorders-Drug Targets · doi:10.2174/1871530315666150316124019 · Cited by 450 · see citing works
AMPK: A Target for Drugs and Natural Products With Effects on Both Diabetes and Cancer
Hardie, D. G. (2013) · Diabetes · doi:10.2337/db13-0368 · Cited by 458 · see citing works
Metformin Action: Concentrations Matter
He, L., & Wondisford, F. E. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.01.003 · Cited by 448 · see citing works
Hirsch, H. A., Iliopoulos, D., & Struhl, K. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1221055110 · Cited by 440 · see citing works
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
Hormonal regulation of hepatic glucose production in health and disease
Lin, H. V., & Accili, D. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.06.003 · Cited by 429 · see citing works
Metformin: Mechanisms in Human Obesity and Weight Loss
Yerevanian, A., & Soukas, A. A. (2019) · Current Obesity Reports · doi:10.1007/s13679-019-00335-3 · Cited by 414 · see citing works
Metformin Activates a Duodenal Ampk-Dependent Pathway to Lower Hepatic Glucose Production in Rats
Duca, F. A., Côté, C. D., Rasmussen, B. A., Zadeh-Tahmasebi, M., Rutter, G. A., Filippi, B. M., & Lam, T. K. T. (2015) · Nature Medicine · doi:10.1038/nm.3787 · Cited by 402 · see citing works
Metformin reduces endogenous reactive oxygen species and associated DNA damage
Algire, C., Moiseeva, O., Deschênes-Simard, X., Amrein, L., Petruccelli, L., Birman, E., Viollet, B., Ferbeyre, G., & Pollak, M. N. (2012) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-11-0536 · Cited by 372 · see citing works
Self-citationMetformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2
De Haes, W., Frooninckx, L., Van Assche, R., Smolders, A., Depuydt, G., Billen, J., Braeckman, B. P., Schoofs, L., & Temmerman, L. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1321776111 · Cited by 355 · see citing works
Justice, J. N., Ferrucci, L., Newman, A. B., Aroda, V. R., Bahnson, J. L., Divers, J., Espeland, M. A., Marcovina, S., Pollak, M. N., Kritchevsky, S. B., et al. (2018) · GeroScience · doi:10.1007/s11357-018-0042-y · Cited by 359 · 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
Song, Y. M., Lee, Y.-H., Kim, J.-W., Ham, D.-S., Kang, E.-S., Cha, B. S., Lee, H. C., & Lee, B.-W. (2015) · Autophagy · doi:10.4161/15548627.2014.984271 · Cited by 332 · 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
Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase
Hunter, R. W., Hughey, C. C., Lantier, L., Sundelin, E. I., Peggie, M., Zeqiraj, E., Sicheri, F., Jessen, N., Wasserman, D. H., & Sakamoto, K. (2018) · Nature Medicine · doi:10.1038/s41591-018-0159-7 · Cited by 313 · see citing works
Self-citationRole of mitochondria in the mechanism(s) of action of metformin
Vial, G., Detaille, D., & Guigas, B. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00294 · Cited by 303 · see citing works
Maintenance of metabolic homeostasis by Sestrin2 and Sestrin3
Lee, J. H., Budanov, A. V., Talukdar, S., Park, E. J., Park, H. L., Park, H.-W., Bandyopadhyay, G., Li, N., Aghajan, M., Jang, I., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.08.004 · Cited by 295 · see citing works
Self-citationGrahame Hardie, D. (2014) · Journal of Internal Medicine · doi:10.1111/joim.12268 · Cited by 285 · 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
Stephenne, X., Foretz, M., Taleux, N., van der Zon, G. C., Sokal, E., Hue, L., Viollet, B., & Guigas, B. (2011) · Diabetologia · doi:10.1007/s00125-011-2311-5 · Cited by 287 · see citing works
Calorie Restriction: Is AMPK a Key Sensor and Effector
Cantó, C., & Auwerx, J. (2011) · Physiology · doi:10.1152/physiol.00010.2011 · Cited by 282 · see citing works
AMP-activated protein kinase regulation and biological actions in the heart
Zaha, V. G., & Young, L. H. (2012) · Circulation Research · doi:10.1161/circresaha.111.255505 · Cited by 279 · see citing works
Metformin as an Anticancer Agent
Vancura, A., Bu, P., Bhagwat, M., Zeng, J., & Vancurova, I. (2018) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2018.07.006 · Cited by 274 · 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-induced mitochondrial Complex I inhibition: facts, uncertainties, and consequences
Fontaine, E. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00753 · Cited by 269 · see citing works
AMP-activated protein kinase: maintaining energy homeostasis at the cellular and whole-body levels
Hardie, D. G. (2014) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071812-161148 · Cited by 281 · see citing works
Bauer, P. V., Duca, F. A., Waise, T. M. Z., Rasmussen, B. A., Abraham, M. A., Dranse, H. J., Puri, A., O’Brien, C. A., & Lam, T. K. T. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2017.09.019 · Cited by 265 · see citing works
<scp>AMPK</scp> α1: A glucose sensor that controls <scp>CD</scp> 8 <scp>T</scp> ‐cell memory
Rolf, J., Zarrouk, M., Finlay, D. K., Foretz, M., Viollet, B., & Cantrell, D. A. (2013) · European Journal of Immunology · doi:10.1002/eji.201243008 · Cited by 245 · see citing works
Self-citationMetformin and Other Biguanides in Oncology: Advancing the Research Agenda
Pollak, M. (2010) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-10-0175 · Cited by 240 · see citing works
An Ancient, Unified Mechanism for Metformin Growth Inhibition in C. Elegans and Cancer
Wu, L., Zhou, B., Oshiro-Rapley, N., Li, M., Paulo, J. A., Webster, C. M., Mou, F., Kacergis, M. C., Talkowski, M. E., Carr, C. E., et al. (2016) · Cell · doi:10.1016/j.cell.2016.11.055 · Cited by 227 · see citing works
Nesti, L., & Natali, A. (2017) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2017.04.009 · Cited by 211 · see citing works
Bryrup, T., Thomsen, C. W., Kern, T., Allin, K. H., Brandslund, I., Jørgensen, N. R., Vestergaard, H., Hansen, T., Hansen, T. H., Pedersen, O., et al. (2019) · Diabetologia · doi:10.1007/s00125-019-4848-7 · Cited by 200 · see citing works
Mitochondrial dysfunction and complications associated with diabetes
Blake, R., & Trounce, I. A. (2014) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2013.11.007 · Cited by 190 · see citing works
Fey, S. J., & Wrzesinski, K. (2012) · Toxicological Sciences · doi:10.1093/toxsci/kfs122 · Cited by 188 · 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
Metformin: 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
Fang, J., Yang, J., Wu, X., Zhang, G., Li, T., Wang, X., Zhang, H., Wang, C., Liu, G., & Wang, L. (2018) · Aging Cell · doi:10.1111/acel.12765 · Cited by 179 · see citing works
Ducommun, S., Deak, M., Sumpton, D., Ford, R. J., Núñez Galindo, A., Kussmann, M., Viollet, B., Steinberg, G. R., Foretz, M., Dayon, L., et al. (2015) · Cellular Signalling · doi:10.1016/j.cellsig.2015.02.008 · Cited by 167 · see citing works
Self-citationNew mechanisms of metformin action: Focusing on mitochondria and the gut
Hur, K. Y., & Lee, M. (2015) · Journal of Diabetes Investigation · doi:10.1111/jdi.12328 · Cited by 161 · see citing works
Kowalski, G. M., & Bruce, C. R. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00165.2014 · Cited by 154 · see citing works
Yin, M., Zhou, J., Gorak, E. J., & Quddus, F. (2013) · The Oncologist · doi:10.1634/theoncologist.2013-0111 · Cited by 157 · see citing works
Serine deprivation enhances antineoplastic activity of biguanides
Gravel, S.-P., Hulea, L., Toban, N., Birman, E., Blouin, M.-J., Zakikhani, M., Zhao, Y., Topisirovic, I., St-Pierre, J., & Pollak, M. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-2643-t · Cited by 138 · see citing works
AMP-activated protein kinase phosphorylates and inactivates liver glycogen synthase
Bultot, L., Guigas, B., Von Wilamowitz-Moellendorff, A., Maisin, L., Vertommen, D., Hussain, N., Beullens, M., Guinovart, J. J., Foretz, M., Viollet, B., et al. (2012) · Biochemical Journal · doi:10.1042/bj20112026 · Cited by 131 · see citing works
Self-citationWilliams, T., Courchet, J., Viollet, B., Brenman, J. E., & Polleux, F. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1013660108 · Cited by 123 · see citing works
Self-citationKim, K. H., Jeong, Y. T., Kim, S. H., Jung, H. S., Park, K. S., Lee, H.-Y., & Lee, M.-S. (2013) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2013.09.026 · Cited by 112 · see citing works
Hirsch, A., Hahn, D., Kempná, P., Hofer, G., Nuoffer, J.-M., Mullis, P. E., & Flück, C. E. (2012) · Endocrinology · doi:10.1210/en.2012-1145 · Cited by 109 · see citing works
Role of AMPK in UVB-induced DNA damage repair and growth control
Wu, C. L., Qiang, L., Han, W., Ming, M., Viollet, B., & He, Y. Y. (2013) · Oncogene · doi:10.1038/onc.2012.279 · Cited by 105 · see citing works
Self-citationNuclear respiratory factor 1 and endurance exercise promote human telomere transcription
Diman, A., Boros, J., Poulain, F., Rodriguez, J., Purnelle, M., Episkopou, H., Bertrand, L., Francaux, M., Deldicque, L., & Decottignies, A. (2016) · Science Advances · doi:10.1126/sciadv.1600031 · Cited by 101 · see citing works
Conti, R., Mannucci, E., Pessotto, P., Tassoni, E., Carminati, P., Giannessi, F., & Arduini, A. (2011) · Diabetes · doi:10.2337/db10-0346 · Cited by 98 · see citing works
Can Metformin Exert as an Active Drug on Endothelial Dysfunction in Diabetic Subjects
Salvatore, T., Pafundi, P. C., Galiero, R., Rinaldi, L., Caturano, A., Vetrano, E., Aprea, C., Albanese, G., Di Martino, A., Ricozzi, C., et al. (2020) · Biomedicines · doi:10.3390/biomedicines9010003 · Cited by 97 · see citing works
Zhou, Z.-Y., Ren, L.-W., Zhan, P., Yang, H.-Y., Chai, D.-D., & Yu, Z.-W. (2016) · Acta Pharmacologica Sinica · doi:10.1038/aps.2016.21 · Cited by 92 · see citing works
Fan, L., Cacicedo, J. M., & Ido, Y. (2020) · Journal of Diabetes Investigation · doi:10.1111/jdi.13303 · Cited by 86 · see citing works
Meta-analysis of studies using metformin as a reducer for liver cancer risk in diabetic patients
Ma, S., Zheng, Y., Xiao, Y., Zhou, P., & Tan, H. (2017) · Medicine · doi:10.1097/md.0000000000006888 · Cited by 89 · see citing works
Metformin for treatment of fragile X syndrome and other neurological disorders
Gantois, I., Popic, J., Khoutorsky, A., & Sonenberg, N. (2019) · Annual Review of Medicine · doi:10.1146/annurev-med-081117-041238 · Cited by 87 · see citing works
P53 coordinates decidual sestrin 2/AMPK/mTORC1 signaling to govern parturition timing
Deng, W., Cha, J., Yuan, J., Haraguchi, H., Bartos, A., Leishman, E., Viollet, B., Bradshaw, H. B., Hirota, Y., & Dey, S. K. (2016) · Journal of Clinical Investigation · doi:10.1172/jci87715 · Cited by 85 · see citing works
Self-citationQuinn, B. J., Dallos, M., Kitagawa, H., Kunnumakkara, A. B., Memmott, R. M., Hollander, M. C., Gills, J. J., & Dennis, P. A. (2013) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-13-0058-t · Cited by 85 · 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
Wang, C., Zhang, T., Liao, Q., Dai, M., Guo, J., Yang, X., Tan, W., Lin, D., Wu, C., & Zhao, Y. (2021) · Protein & Cell · doi:10.1007/s13238-020-00760-4 · Cited by 82 · see citing works
Health benefits of late-onset metformin treatment every other week in mice
Alfaras, I., Mitchell, S. J., Mora, H., Lugo, D. R., Warren, A., Navas-Enamorado, I., Hoffmann, V., Hine, C., Mitchell, J. R., Le Couteur, D. G., et al. (2017) · npj Aging and Mechanisms of Disease · doi:10.1038/s41514-017-0018-7 · Cited by 68 · see citing works
Metformin from mother to unborn child-are there unwarranted effects?
Nguyen, L., Chan, S.-Y., & Teo, A. K. K. (2018) · EBioMedicine · doi:10.1016/j.ebiom.2018.08.047 · Cited by 67 · see citing works
Zhu, L., Shi, J., Luu, T. N., Neuman, J. C., Trefts, E., Yu, S., Palmisano, B. T., Wasserman, D. H., Linton, M. F., & Stafford, J. M. (2018) · Molecular Metabolism · doi:10.1016/j.molmet.2017.12.012 · Cited by 66 · see citing works
New Insights Into the Anti-Diabetic Actions of Metformin: From the Liver to the Gut
Wu, T., Horowitz, M., & Rayner, C. K. (2017) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2017.1273769 · Cited by 64 · see citing works
Salomäki, H., Heinäniemi, M., Vähätalo, L. H., Ailanen, L., Eerola, K., Ruohonen, S. T., Pesonen, U., & Koulu, M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0115778 · Cited by 63 · see citing works
Why 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
Kristensen, J. M., Larsen, S., Helge, J. W., Dela, F., & Wojtaszewski, J. F. P. (2013) · PLoS ONE · doi:10.1371/journal.pone.0053533 · Cited by 48 · see citing works
Ghosh, S., Lakshmanan, A. P., Hwang, M. J., Kubba, H., Mushannen, A., Triggle, C. R., & Ding, H. (2015) · Biochemical Pharmacology · doi:10.1016/j.bcp.2015.10.008 · Cited by 45 · see citing works
Augmenting energy expenditure by mitochondrial uncoupling: A role of AMP-activated protein kinase
Klaus, S., Keipert, S., Rossmeisl, M., & Kopecky, J. (2012) · Genes & Nutrition · doi:10.1007/s12263-011-0260-8 · Cited by 44 · 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
Therapeutic Manipulation of Ageing: Repurposing Old Dogs and Discovering New Tricks
Mallikarjun, V., & Swift, J. (2016) · EBioMedicine · doi:10.1016/j.ebiom.2016.11.020 · Cited by 14 · see citing works
- Authors
- Foretz, M., Hébrard, S., Leclerc, J., Zarrinpashneh, E., Soty, M., Mithieux, G., Sakamoto, K., Andreelli, F., & Viollet, B.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Institut Cochin (FR)
- MRC Protein Phosphorylation and Ubiquitylation Unit (GB)
- Nutrition, Diabète et Cerveau (FR)
- Venue
- Journal of Clinical Investigation
- Published
- 2010-07-01
- Volume
- 120
- Issue
- 7
- Pages
- 2355-2369
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2898585
- OpenAlex
- W2092340120
- Cited by
- 1,181
- References
- 69
- Citations by year
- 2026: 17 · 2025: 42 · 2024: 51 · 2023: 58 · 2022: 68 · 2021: 77 · 2020: 78 · 2019: 78 · 2018: 89 · 2017: 82 · 2016: 90 · 2015: 90 · 2014: 108 · 2013: 90 · 2012: 80
- FWCI
- 32.98
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- University of Dundee
- Diabetes UK (07/0003529)
- European Commission (LSHMCT-2004-005272)
- Agence Nationale de la Recherche (ANR-06-PHYS-0026)
- Swedish Foundation for International Cooperation in Research and Higher Education
- Association pour la Recherche sur le Diabète
- U.S. Public Health Service (07/0003529)
- Medical Research Council (07/0003529)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
- Keywords
- metformin, hepatic gluconeogenesis, LKB1, AMPK, intracellular ATP, glucose-6-phosphatase, phosphoenolpyruvate carboxykinase, PGC-1α, type 2 diabetes, hypoglycemic effect
- MeSH terms
- Animals, Diabetes Mellitus, Type 2, Gluconeogenesis, Glucose, Glucose-6-Phosphatase, Hyperglycemia, Hypoglycemic Agents, Liver, Metformin, Mice, Inbred C57BL, Up-Regulation, Protein Serine-Threonine Kinases, Mice, Knockout, Phosphoenolpyruvate Carboxykinase (ATP), Hepatocytes, Mice, AMP-Activated Protein Kinases
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