Metformin Activates a Duodenal Ampk-Dependent Pathway to Lower Hepatic Glucose Production in Rats
Open accessAbstract
Metformin is a first-line therapeutic option for the treatment of type 2 diabetes, even though its underlying mechanisms of action are relatively unclear. Metformin lowers blood glucose levels by inhibiting hepatic glucose production (HGP), an effect originally postulated to be due to a hepatic AMP-activated protein kinase (AMPK)-dependent mechanism. However, studies have questioned the contribution of hepatic AMPK to the effects of metformin on lowering hyperglycemia, and a gut-brain-liver axis that mediates intestinal nutrient- and hormone-induced lowering of HGP has been identified. Thus, it is possible that metformin affects HGP through this inter-organ crosstalk. Here we show that intraduodenal infusion of metformin for 50 min activated duodenal mucosal Ampk and lowered HGP in a rat 3 d high fat diet (HFD)-induced model of insulin resistance. Inhibition of duodenal Ampk negated the HGP-lowering effect of intraduodenal metformin, and both duodenal glucagon-like peptide-1 receptor (Glp-1r)-protein kinase A (Pka) signaling and a neuronal-mediated gut-brain-liver pathway were required for metformin to lower HGP. Preabsorptive metformin also lowered HGP in rat models of 28 d HFD-induced obesity and insulin resistance and nicotinamide (NA)-streptozotocin (STZ)-HFD-induced type 2 diabetes. In an unclamped setting, inhibition of duodenal Ampk reduced the glucose-lowering effects of a bolus metformin treatment in rat models of diabetes. These findings show that, in rat models of both obesity and diabetes, metformin activates a previously unappreciated duodenal Ampk-dependent pathway to lower HGP and plasma glucose levels.
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There are extra-hepatic sites of action of metformin with the gut being a major contributor to its clinical benefits as an anti-hyperglycemic drug via modulating glucagon-like peptide 1 levels by a duodenal AMPK-mediated pathway, as well as effects resulting from modulating the microbiota.
“We now know there are extra-hepatic sites of action of metformin with the gut being a major contributor to its clinical benefits as an anti-hyperglycemic drug via modulating glucagon-like peptide 1 (GLP-1) levels by a duodenal AMPK-mediated pathway, as well as effects resulting from modulating the microbiota (25–29).”
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 [25]
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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
The selectivity of protein kinase inhibitors: a further update
Bain, J., Plater, L., Elliott, M., Shpiro, N., Hastie, C. J., McLauchlan, H., Klevernic, I. V., Arthur, J. S. C., Alessi, D. R., & Cohen, P. (2007) · Biochemical Journal · doi:10.1042/bj20070797 · Cited by 2,522 · 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
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
Shin, N.-R., Lee, J.-C., Lee, H.-Y., Kim, M.-S., Whon, T. W., Lee, M.-S., & Bae, J.-W. (2014) · Gut · doi:10.1136/gutjnl-2012-303839 · Cited by 1,550 · 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
Clinical pharmacokinetics of metformin
Graham, G. G., Punt, J., Arora, M., Day, R. O., Doogue, M. P., Duong, J. K., Furlong, T. J., Greenfield, J. R., Greenup, L. C., Kirkpatrick, C. M., et al. (2011) · Clinical Pharmacokinetics · doi:10.2165/11534750-000000000-00000 · Cited by 1,318 · 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
Foretz, M., Hébrard, S., Leclerc, J., Zarrinpashneh, E., Soty, M., Mithieux, G., Sakamoto, K., Andreelli, F., & Viollet, B. (2010) · Journal of Clinical Investigation · doi:10.1172/jci40671 · Cited by 1,181 · see citing works
Metabolic effects of metformin in non-insulin-dependent diabetes mellitus
Stumvoll, M., Nurjhan, N., Perriello, G., Dailey, G., & Gerich, J. E. (1995) · New England Journal of Medicine · doi:10.1056/nejm199508313330903 · Cited by 1,148 · 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
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
Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP
Miller, R., Chu, Q., Xie, J., Foretz, M., Viollet, B., & Birnbaum, M. J. (2013) · Nature · doi:10.1038/nature11808 · Cited by 828 · see citing works
Use of Cells Expressing γ Subunit Variants to Identify Diverse Mechanisms of AMPK Activation
Hawley, S. A., Ross, F. A., Chevtzoff, C., Green, K. A., Evans, A., Fogarty, S., Towler, M. C., Brown, L. J., Ogunbayo, O. A., Evans, A. M., et al. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.04.001 · Cited by 773 · 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
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
Richards, P., Parker, H. E., Adriaenssens, A. E., Hodgson, J. M., Cork, S. C., Trapp, S., Gribble, F. M., & Reimann, F. (2014) · Diabetes · doi:10.2337/db13-1440 · Cited by 472 · see citing works
Yusta, B., Baggio, L. L., Estall, J. L., Koehler, J. A., Holland, D. P., Li, H., Pipeleers, D., Ling, Z., & Drucker, D. J. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.10.001 · Cited by 444 · see citing works
Accumulation 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
Habib, A. M., Richards, P., Cairns, L. S., Rogers, G. J., Bannon, C. A. M., Parker, H. E., Morley, T. C. E., Yeo, G. S. H., Reimann, F. M., & Gribble, F. M. (2012) · Endocrinology · doi:10.1210/en.2011-2170 · Cited by 382 · see citing works
Overfeeding Rapidly Induces Leptin and Insulin Resistance
Wang, J., Obici, S., Morgan, K., Barzilai, N., Feng, Z., & Rossetti, L. (2001) · Diabetes · doi:10.2337/diabetes.50.12.2786 · Cited by 355 · see citing works
Dale, S. J., Wilson, W. A., Edelman, A. M., & Hardie, D. G. (1995) · FEBS Letters · doi:10.1016/0014-5793(95)00172-6 · Cited by 324 · see citing works
Deconstructing Type 2 Diabetes
Taylor, S. I. (1999) · Cell · doi:10.1016/s0092-8674(00)80709-6 · Cited by 310 · see citing works
Maida, A., Lamont, B. J., Cao, X., & Drucker, D. J. (2010) · Diabetologia · doi:10.1007/s00125-010-1937-z · Cited by 293 · see citing works
Upper intestinal lipids trigger a gut–brain–liver axis to regulate glucose production
Wang, P. Y. T., Caspi, L., Lam, C., Chari, M., Li, X., Light, P. E., Juárez, R. G., Ang, M. L. T., Schwartz, G. J., & Lam, T. K. T. (2008) · Nature · doi:10.1038/nature06852 · Cited by 293 · see citing works
Self-citationXavier, G. D. S., Leclerc, I., Váradi, A., Tsuboi, T., MOULE, S. K., & Rutter, G. A. (2003) · Biochemical Journal · doi:10.1042/bj20021812 · Cited by 257 · see citing works
Self-citationMeta-analysis: metformin treatment in persons at risk for diabetes mellitus
Salpeter, S. R., Buckley, N. S., Kahn, J. A., & Salpeter, E. E. (2008) · The American Journal of Medicine · doi:10.1016/j.amjmed.2007.09.016 · Cited by 248 · see citing works
Breen, D. M., Rasmussen, B. A., Kokorovic, A., Wang, R., Cheung, G. W. C., & Lam, T. K. T. (2012) · Nature Medicine · doi:10.1038/nm.2745 · Cited by 209 · see citing works
Self-citationIntestinal Cholecystokinin Controls Glucose Production through a Neuronal Network
Cheung, G. W. C., Kokorovic, A., Lam, C., Chari, M., & Lam, T. K. T. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.07.005 · Cited by 179 · see citing works
Self-citationSamuel, V. T., Beddow, S. A., Iwasaki, T., Zhang, X., Chu, X., Still, C. D., Gerhard, G. S., & Shulman, G. I. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0812547106 · Cited by 176 · see citing works
Activation of hypothalamic S6 kinase mediates diet-induced hepatic insulin resistance in rats
Ono, H., Pocai, A., Wang, Y., Sakoda, H., Asano, T., Backer, J., Schwartz, G. J., & Rossetti, L. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34277 · Cited by 175 · see citing works
Mulherin, A. J., Oh, A., Kim, H., Grieco, A. J., Lauffer, L. M., & Brubaker, P. L. (2011) · Endocrinology · doi:10.1210/en.2011-1485 · Cited by 158 · see citing works
Stepensky, D., Friedman, M., Raz, I., & Hoffman, A. (2002) · Drug Metabolism and Disposition · doi:10.1124/dmd.30.8.861 · Cited by 135 · see citing works
Choi, Y. H., Kim, S. G., & Lee, M. G. (2006) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.20744 · Cited by 129 · see citing works
Neuronal regulation of homeostasis by nutrient sensing
Lam, T. K. T. (2010) · Nature Medicine · doi:10.1038/nm0410-392 · Cited by 125 · see citing works
Self-citationPollak, M. (2014) · Nature Medicine · doi:10.1038/nm.3596 · Cited by 115 · see citing works
Effects of Metformin on Lactate Uptake and Gluconeogenesis in the Perfused Rat Liver
Radziuk, J., Zhang, Z. M., Wiernsperger, N. F., & Pye, S. (1997) · Diabetes · doi:10.2337/diab.46.9.1406 · Cited by 111 · see citing works
AMP-Activated Protein Kinase Induces p53 by Phosphorylating MDMX and Inhibiting Its Activity
He, G., Zhang, Y.-W., Lee, J., Zeng, S. X., Wang, Y. V., Luo, Z., Dong, X. C., Viollet, B., Wahl, G. M., & Lu, H. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.00670-13 · Cited by 105 · see citing works
Insulin Activates Erk1/2 Signaling in the Dorsal Vagal Complex to Inhibit Glucose Production
Filippi, B., Yang, C. S., Tang, C., & Lam, T. K. T. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.09.005 · Cited by 104 · see citing works
Self-citationVardarli, I., Arndt, E., Deacon, C. F., Holst, J. J., & Nauck, M. A. (2013) · Diabetes · doi:10.2337/db13-0805 · Cited by 90 · see citing works
AMPK in the Small Intestine in Normal and Pathophysiological Conditions
Harmel, É., Grenier, É., Ouadda, A. B. D., Elchebly, M., Ziv, E., Beaulieu, J., Sané, A. T., Spahis, S., Laville, M., & Levy, E. H. (2014) · Endocrinology · doi:10.1210/en.2013-1750 · Cited by 50 · see citing works
Rasmussen, B. A., Breen, D. M., Luo, P., Cheung, G. W. C., Yang, C. S., Sun, B., Kokorovic, A., Rong, W., & Lam, T. K. T. (2012) · Gastroenterology · doi:10.1053/j.gastro.2011.12.053 · Cited by 49 · see citing works
Self-citationJejunal Leptin-PI3K Signaling Lowers Glucose Production
Rasmussen, B. A., Breen, D. M., Duca, F. A., Côté, C. D., Zadeh‐Tahmasebi, M., Filippi, B., & Lam, T. K. T. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.11.014 · Cited by 32 · see citing works
Self-citationDuodenal Mucosal Protein Kinase C-δ Regulates Glucose Production in Rats
Kokorovic, A., Cheung, G. W. C., Breen, D. M., Chari, M., Lam, C., & Lam, T. K. T. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.06.042 · Cited by 31 · see citing works
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Rena, G., Hardie, D. G., & Pearson, E. R. (2017) · Diabetologia · doi:10.1007/s00125-017-4342-z · Cited by 2,287 · see citing works
AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance
Garcia, D., & Shaw, R. J. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.05.032 · Cited by 1,997 · 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 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
Metabolic Control of Longevity
López-Otín, C., Galluzzi, L., Freije, J. M. P., Madeo, F., & Kroemer, G. (2016) · Cell · doi:10.1016/j.cell.2016.07.031 · Cited by 753 · see citing works
Metformin and the gastrointestinal tract
McCreight, L. J., Bailey, C. J., & Pearson, E. R. (2016) · Diabetologia · doi:10.1007/s00125-015-3844-9 · Cited by 733 · see citing works
Metformin: update on mechanisms of action and repurposing potential
Foretz, M., Guigas, B., & Viollet, B. (2023) · Nature Reviews Endocrinology · doi:10.1038/s41574-023-00833-4 · Cited by 744 · 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
Understanding 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
Madeo, F., Carmona-Gutierrez, D., Hofer, S. J., & Kroemer, G. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.01.018 · Cited by 630 · see citing works
Low-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
AMPK as a Therapeutic Target for Treating Metabolic Diseases
Day, E. A., Ford, R. J., & Steinberg, G. R. (2017) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2017.05.004 · Cited by 620 · 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
Xian, H., Liu, Y., Nilsson, A. R., Gatchalian, R., Crother, T. R., Tourtellotte, W. G., Zhang, Y., Alemán-Muench, G. R., Lewis, G. M., Chen, W., et al. (2021) · Immunity · doi:10.1016/j.immuni.2021.05.004 · Cited by 407 · see citing works
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Yang, C. S., Zhang, J., Zhang, L., Huang, J., & Wang, Y. (2015) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201500428 · Cited by 384 · 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
Higurashi, T., Hosono, K., Takahashi, H., Komiya, Y., Umezawa, S., Sakai, E., Uchiyama, T., Taniguchi, L., Hata, Y., Uchiyama, S., et al. (2016) · The Lancet Oncology · doi:10.1016/s1470-2045(15)00565-3 · Cited by 331 · see citing works
Insulin resistance and Parkinson’s disease: A new target for disease modification?
Athauda, D. S., & Foltynie, T. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.10.001 · Cited by 333 · see citing works
Metformin: a review of its potential indications
Wang, Y., He, S., Feng, X., Cheng, J. Q., Luo, Y.-T., Tian, L., & Huang, Q. (2017) · Drug Design Development and Therapy · doi:10.2147/dddt.s141675 · Cited by 324 · 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
Day, E. A., Ford, R. J., Smith, B. K., Mohammadi-Shemirani, P., Morrow, M. R., Gutgesell, R. M., Lu, R., Raphenya, A. R., Kabiri, M., McArthur, A. G., et al. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0146-4 · Cited by 307 · see citing works
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Madiraju, A. K., Qiu, Y., Perry, R. J., Rahimi, Y., Zhang, X., Zhang, D., Camporez, J. P., Cline, G. W., Butrico, G. M., Kemp, B. E., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0125-4 · Cited by 297 · see citing works
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Garcia, D., Hellberg, K., Chaix, A., Wallace, M., Herzig, S., Badur, M. G., Lin, T. C., Shokhirev, M. N., Pinto, A. F. M., Ross, D. S., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2018.12.036 · Cited by 294 · 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
Drug-microbiota interactions: an emerging priority for precision medicine
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Role of the gut-brain axis in energy and glucose metabolism
Wachsmuth, H. R., Weninger, S. N., & Duca, F. A. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-021-00677-w · Cited by 269 · see citing works
Self-citationCokorinos, E., Delmore, J. E., Reyes, A. R., Albuquerque, B., Kjøbsted, R., Eskesen, N. O., Tran, J.-L., Jatkar, A., Cialdea, K., Esquejo, R. M., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.04.010 · Cited by 267 · 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
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Han, H., Hou, Y., Chen, X., Zhang, P., Kang, M., Jin, Q., Ji, J., & Gao, M. (2020) · Journal of the American Chemical Society · doi:10.1021/jacs.0c00650 · Cited by 232 · 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
Current understanding of metformin effect on the control of hyperglycemia in diabetes
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Iwasaki, Y., Sendo, M., Dezaki, K., Hira, T., Sato, T., Nakata, M., Goswami, C., Aoki, R., Arai, T., Kumari, P., et al. (2018) · Nature Communications · doi:10.1038/s41467-017-02488-y · Cited by 200 · 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
Apostolova, N., Iannantuoni, F., Gruevska, A., Muntané, J., Rocha, M., & Víctor, V. M. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101517 · Cited by 201 · see citing works
Metformin‐mediated increase in DICER1 regulates microRNA expression and cellular senescence
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Gonzalez, A., Krieg, R. J., Massey, H. D., Carl, D. E., Ghosh, S., Gehr, T. W. B., & Ghosh, S. S. (2018) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfy238 · Cited by 193 · see citing works
Metformin in aging and aging-related diseases: clinical applications and relevant mechanisms
Chen, S., Gan, D., Lin, S., Zhong, Y., Chen, M., Zou, X., Shao, Z., & Xiao, G. (2022) · Theranostics · doi:10.7150/thno.71360 · Cited by 197 · see citing works
Causality of small and large intestinal microbiota in weight regulation and insulin resistance
Scheithauer, T. P. M., Dallinga-Thie, G. M., de Vos, W. M., Nieuwdorp, M., & van Raalte, D. H. (2016) · Molecular Metabolism · doi:10.1016/j.molmet.2016.06.002 · Cited by 188 · see citing works
“Metformin activates a duodenal AMPK dependent pathway to lower hepatic glucose production [78].”
BackgroundNowak-Sliwinska, P. M., Scapozza, L., & Altaba, A. R. I. (2019) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2019.04.005 · Cited by 183 · see citing works
The Current and Potential Therapeutic Use of Metformin—The Good Old Drug
Drzewoski, J., & Hanefeld, M. (2021) · Pharmaceuticals · doi:10.3390/ph14020122 · Cited by 165 · see citing works
Metformin selectively targets redox control of complex I energy transduction
Cameron, A., Logie, L., Patel, K. A., Erhardt, S., Bacon, S., Middleton, P. K., Harthill, J. E., Forteath, C., Coats, J. T., Kerr, C., et al. (2017) · Redox Biology · doi:10.1016/j.redox.2017.08.018 · Cited by 153 · see citing works
Lee, C. B., Chae, S. U., Jo, S. J., Jerng, U. M., & Bae, S. K. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073566 · Cited by 149 · see citing works
Côté, C. D., Rasmussen, B. A., Duca, F. A., Zadeh‐Tahmasebi, M., Baur, J. A., Daljeet, M., Breen, D. M., Filippi, B., & Lam, T. K. T. (2015) · Nature Medicine · doi:10.1038/nm.3821 · Cited by 148 · see citing works
Self-citationGormsen, L. C., Sundelin, E. I. O., Jensen, J., Vendelbo, M. H., Jakobsen, S., Munk, O. L., Christensen, M. M. H., Brøsen, K., Frøkiær, J., & Jessen, N. (2016) · Journal of Nuclear Medicine · doi:10.2967/jnumed.116.177774 · Cited by 145 · see citing works
van Stee, M. F., de Graaf, A. A., & Groen, A. K. (2018) · Cardiovascular Diabetology · doi:10.1186/s12933-018-0738-4 · Cited by 147 · 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
The progress and perspective of strategies to improve tumor penetration of nanomedicines
Hu, J., Yuan, X., Wang, F., Gao, H., Liu, X., & Zhang, W. (2020) · Chinese Chemical Letters · doi:10.1016/j.cclet.2020.11.006 · Cited by 144 · see citing works
Xie, S., Liu, S., Zhang, T., Shi, W., Xing, Y., Fang, W., Zhang, M., Chen, M.-Y., Xu, S., Fan, M.-Q., et al. (2023) · Circulation · doi:10.1161/circulationaha.123.065603 · Cited by 143 · see citing works
The metabolic role of vagal afferent innervation
Waise, T. M. Z., Dranse, H. J., & Lam, T. K. T. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0062-1 · Cited by 140 · see citing works
Self-citationMetformin and gut microbiota: their interactions and their impact on diabetes
Vallianou, N. G., Stratigou, T., & Tsagarakis, S. (2019) · Hormones · doi:10.1007/s42000-019-00093-w · Cited by 138 · see citing works
Metformin Improves Functional Recovery After Spinal Cord Injury via Autophagy Flux Stimulation
Zhang, D., Xuan, J., Zheng, B., Zhou, Y., Lin, Y., Wu, Y., Zhou, Y., Huang, Y.-X., Wang, Q., Shen, L., et al. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-9895-1 · Cited by 134 · see citing works
Metformin acutely lowers blood glucose levels by inhibition of intestinal glucose transport
Horakova, O., Kroupova, P., Bardová, K., Buresova, J., Janovská, P., Kopecký, J., & Rossmeisl, M. (2019) · Scientific Reports · doi:10.1038/s41598-019-42531-0 · Cited by 131 · see citing works
DeFronzo, R. A., Buse, J. B., Kim, T., Burns, C. M., Skare, S., Baron, A., & Fineman, M. S. (2016) · Diabetologia · doi:10.1007/s00125-016-3992-6 · Cited by 131 · see citing works
Bi-directional drug-microbiome interactions of anti-diabetics
Whang, A., Nagpal, R., & Yadav, H. (2018) · EBioMedicine · doi:10.1016/j.ebiom.2018.11.046 · Cited by 122 · see citing works
Mitochondrial Regulation of Stem Cells in Bone Homeostasis
Zheng, C., Sui, B., Qiu, X., Hu, C., & Jin, Y. J. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2019.04.008 · Cited by 121 · see citing works
The road ahead for health and lifespan interventions
Gonzalez-Freire, M., Diaz-Ruiz, A., Hauser, D., Martinez-Romero, J., Ferrucci, L., Bernier, M., & de Cabo, R. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101037 · Cited by 118 · 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
Berberine Attenuates Intestinal Mucosal Barrier Dysfunction in Type 2 Diabetic Rats
Gong, J., Hu, M., Huang, Z., Fang, K., Wang, D., Chen, Q., Li, J., Yang, D., Zou, X. G., Xu, L., et al. (2017) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00042 · Cited by 116 · see citing works
Rodriguez, J., Hiel, S., & Delzenne, N. M. (2018) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0000000000000468 · Cited by 113 · see citing works
Prattichizzo, F., Giuliani, A., Mensa’, E., Sabbatinelli, J., Nigris, V. D., Rippo, M. R., Sala, L. L., Procopio, A. D., Olivieri, F., & Ceriello, A. (2018) · Ageing Research Reviews · doi:10.1016/j.arr.2018.10.003 · Cited by 111 · see citing works
Variants in Pharmacokinetic Transporters and Glycemic Response to Metformin: A Metgen Meta‐Analysis
Dujić, T., Zhou, K., Yee, S. W., van Leeuwen, N., de Keyser, C., Javorský, M., Goswami, S., Zaharenko, L., Christensen, M. M. H., Out, M., et al. (2016) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.567 · Cited by 110 · see citing works
Bauer, P. V., Duca, F. A., Waise, T. M. Z., Dranse, H. J., Rasmussen, B. A., Puri, A., Rasti, M., O'Brien, C. A., & Lam, T. K. T. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.01.013 · Cited by 104 · see citing works
Self-citationHasanvand, A. (2022) · Inflammopharmacology · doi:10.1007/s10787-022-00980-6 · Cited by 105 · see citing works
Metformin, beyond an insulin sensitizer, targeting heart and pancreatic β cells.
Yang, X., Xu, Z., Zhang, C., Cai, Z.-X., & Zhang, J.-J. (2017) · Biochimica et Biophysica Acta - Molecular Basis of Disease · doi:10.1016/j.bbadis.2016.09.019 · Cited by 102 · see citing works
Glucagon‐like Peptide‐2 and the Regulation of Intestinal Growth and Function
Brubaker, P. L. (2018) · Comprehensive physiology · doi:10.1002/cphy.c170055 · Cited by 104 · see citing works
Glyoxalase 1 Modulation in Obesity and Diabetes
Rabbani, N., & Thornalley, P. J. (2019) · Antioxidants & Redox Signaling · doi:10.1089/ars.2017.7424 · Cited by 102 · see citing works
New therapeutic approaches for the treatment of obesity
Saltiel, A. R. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aad1811 · Cited by 100 · see citing works
A preclinical overview of metformin for the treatment of type 2 diabetes
Zhou, T., Xu, X., Du, M., Zhao, T., & Wang, J. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.07.085 · Cited by 101 · see citing works
AMPK and the Endocrine Control of Metabolism
Townsend, L. K., & Steinberg, G. R. (2023) · Endocrine Reviews · doi:10.1210/endrev/bnad012 · Cited by 107 · see citing works
The effects of metformin on gut microbiota and the immune system as research frontiers
Pollak, M. (2017) · Diabetologia · doi:10.1007/s00125-017-4352-x · Cited by 98 · see citing works
Akkermansia muciniphila: a potential candidate for ameliorating metabolic diseases
Niu, H., Zhou, M., Zogona, D., Xing, Z., Wu, T., Chen, R., Cui, D., Liang, F., & Xu, X. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1370658 · Cited by 98 · see citing works
Molecular Basis of the Beneficial Actions of Resveratrol
Repossi, G., Das, U. N., & Eynard, A. R. (2020) · Archives of Medical Research · doi:10.1016/j.arcmed.2020.01.010 · Cited by 96 · see citing works
The emerging role of the small intestinal microbiota in human health and disease
Ruigrok, R. A. A. A., Weersma, R. K., & Vila, A. V. (2023) · Gut Microbes · doi:10.1080/19490976.2023.2201155 · Cited by 96 · see citing works
Metformin: New Preparations and Nonglycemic Benefits
Fujita, Y., & Inagaki, N. (2017) · Current Diabetes Reports · doi:10.1007/s11892-017-0829-8 · Cited by 91 · see citing works
Macroautophagy and aging: The impact of cellular recycling on health and longevity
Nieto-Torres, J. L., & Hansen, M. (2021) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2021.101020 · Cited by 91 · see citing works
Jensen, J., Sundelin, E. I. O., Jakobsen, S., Gormsen, L. C., Munk, O. L., Frøkiær, J., & Jessen, N. (2016) · Diabetes · doi:10.2337/db16-0032 · Cited by 90 · see citing works
Immunologic impact of the intestine in metabolic disease
Winer, D. A., Winer, S., Dranse, H. J., & Lam, T. K. T. (2017) · Journal of Clinical Investigation · doi:10.1172/jci88879 · Cited by 88 · see citing works
Self-citationZhang, S., Bruce, K., Danaei, Z., Li, R. J. W., Barros, D. R., Kuah, R., Lim, Y.-M., Mariani, L. H., Cherney, D. Z. I., Chiu, J. F. M., et al. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.03.014 · Cited by 88 · see citing works
Self-citationPromise and challenges for direct small molecule AMPK activators
Olivier, S., Foretz, M., & Viollet, B. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.01.049 · 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
Mechanism of glucose-lowering by metformin in type 2 diabetes: Role of bile acids
Sansome, D. J., Xie, C., Veedfald, S., Horowitz, M., Rayner, C. K., & Wu, T. (2020) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.13869 · Cited by 84 · see citing works
Xiao, D., Yu, G., Li, X., Yin, J., Zheng, W., Qiu, X., Xiao, L., Liu, R., Wang, S., Gong, W., et al. (2016) · International Journal of Endocrinology · doi:10.1155/2016/4350712 · Cited by 83 · see citing works
Metformin in therapeutic applications in human diseases: its mechanism of action and clinical study
Du, Y., Zhu, Y., Zhou, Y., Ding, J., & Liu, J. (2022) · Molecular Biomedicine · doi:10.1186/s43556-022-00108-w · Cited by 82 · see citing works
The Role of AMPK Signaling in Brown Adipose Tissue Activation
van der Vaart, J. I., Boon, M. R., & Houtkooper, R. H. (2021) · Cells · doi:10.3390/cells10051122 · Cited by 82 · see citing works
Li, N., Zhou, T. G., & Fei, E. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23158281 · Cited by 83 · see citing works
Szymczak-Pajor, I., Wenclewska, S., & Śliwińska, A. (2022) · Pharmaceuticals · doi:10.3390/ph15070810 · Cited by 81 · see citing works
Yan, Y., Li, M., Lin, J., Ji, Y., Wang, K., Yan, D., Shen, Y., Wang, W., Huang, Z., Jiang, H., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.947387 · Cited by 81 · see citing works
Metformin acts in the gut and induces gut-liver crosstalk
Tobar, N., Rocha, G. Z., Santos, A., Guadagnini, D., Assalin, H. B., de Camargo, J. A., Gonçalves, A. E. S. S., Pallis, F. R., Oliveira, A. G., Rocco, S. A., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2211933120 · Cited by 78 · see citing works
Intestinal AMPK modulation of microbiota mediates crosstalk with brown fat to control thermogenesis
Zhang, E., Jin, L., Wang, Y., Tu, J., Zheng, R., Ding, L., Fang, Z., Fan, M., Al-Abdullah, I., Natarajan, R., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-28743-5 · Cited by 76 · see citing works
Neural ageing and synaptic plasticity: prioritizing brain health in healthy longevity
Navakkode, S., & Kennedy, B. K. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1428244 · Cited by 75 · see citing works
Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation
Cortés, M., Brischetto, A., Martínez-Campanario, M. C., Ninfali, C., Domínguez, V., Fernández, S., Celis, R., Esteve‐Codina, A., Lozano, J. J., Sidorova, J., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-42277-4 · Cited by 75 · see citing works
Wulsin, L. R., Herman, J. P., & Thayer, J. F. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.12.010 · Cited by 73 · see citing works
Maniar, K., Moideen, A., Mittal, A., Patil, A., Chakrabarti, A., & Banerjee, D. (2016) · Pharmacological Research · doi:10.1016/j.phrs.2016.12.003 · Cited by 75 · see citing works
Shpakov, A. O. (2021) · Pharmaceuticals · doi:10.3390/ph14010042 · Cited by 81 · see citing works
Lactate and Myocardiac Energy Metabolism
Dong, S., Qian, L., Cheng, Z., Chen, C., Wang, K., Hu, S., Zhang, X., & Wu, T. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.715081 · Cited by 74 · see citing works
- Authors
- Duca, F. A., Côté, C. D., Rasmussen, B. A., Zadeh-Tahmasebi, M., Rutter, G. A., Filippi, B. M., & Lam, T. K. T.
- Affiliations
- University Health Network (CA)
- Hammersmith Hospital (GB)
- Corresponding author
- Lam, Tony K T
- Venue
- Nature Medicine
- Published
- 2015-04-06
- Volume
- 21
- Issue
- 5
- Pages
- 506-511
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6104807
- OpenAlex
- W1981432724
- Cited by
- 402
- References
- 45
- Citations by year
- 2026: 13 · 2025: 30 · 2024: 34 · 2023: 28 · 2022: 34 · 2021: 40 · 2020: 53 · 2019: 31 · 2018: 42 · 2017: 35 · 2016: 47 · 2015: 14
- FWCI
- 19.98
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-02-04)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Wellcome Trust (098424, WT098424AIA)
- Canadian Institutes of Health Research (MOP-82701)
- Medical Research Council (MR/K001981/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- metformin, hepatic glucose production, AMPK, duodenal mucosa, GLP-1 receptor, protein kinase A, insulin resistance, type 2 diabetes, obesity, high-fat diet, glucose-lowering mechanism
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Animals, Blood Glucose, Diabetes Mellitus, Type 2, Duodenum, Glucose, Humans, Insulin, Insulin Resistance, Liver, Male, Metformin, Niacinamide, Obesity, Glucose Clamp Technique, Signal Transduction, Gene Expression Regulation, Enzymologic, Rats, Sprague-Dawley, Receptors, Glucagon, Rats, AMP-Activated Protein Kinases, HEK293 Cells
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