Metformin: update on mechanisms of action and repurposing potential.

Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101500078 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1759-5037 (Electronic) Linking ISSN: 17595029 NLM ISO Abbreviation: Nat Rev Endocrinol Subsets: MEDLINE

Original Publication: London : Nature Pub. Group

Metformin*/therapeutic use ; Metformin*/pharmacology ; Diabetes Mellitus, Type 2*/drug therapy ; COVID-19*; Humans ; Hypoglycemic Agents/pharmacology ; Hypoglycemic Agents/therapeutic use ; Glucose

Currently, metformin is the first-line medication to treat type 2 diabetes mellitus (T2DM) in most guidelines and is used daily by >200 million patients. Surprisingly, the mechanisms underlying its therapeutic action are complex and are still not fully understood. Early evidence highlighted the liver as the major organ involved in the effect of metformin on reducing blood levels of glucose. However, increasing evidence points towards other sites of action that might also have an important role, including the gastrointestinal tract, the gut microbial communities and the tissue-resident immune cells. At the molecular level, it seems that the mechanisms of action vary depending on the dose of metformin used and duration of treatment. Initial studies have shown that metformin targets hepatic mitochondria; however, the identification of a novel target at low concentrations of metformin at the lysosome surface might reveal a new mechanism of action. Based on the efficacy and safety records in T2DM, attention has been given to the repurposing of metformin as part of adjunct therapy for the treatment of cancer, age-related diseases, inflammatory diseases and COVID-19. In this Review, we highlight the latest advances in our understanding of the mechanisms of action of metformin and discuss potential emerging novel therapeutic uses.
(© 2023. Springer Nature Limited.)

Schernthaner, G. & Schernthaner, G. H. The right place for metformin today. Diabetes Res. Clin. Pract. 159, 107946 (2020). (PMID: 3177874610.1016/j.diabres.2019.107946)
Ahmad, E. et al. Where does metformin stand in modern day management of type 2 diabetes? Pharmaceuticals 13, 427 (2020). (PMID: 33261058776152210.3390/ph13120427)
Triggle, C. R. et al. Metformin: Is it a drug for all reasons and diseases? Metabolism 133, 155223 (2022). (PMID: 3564074310.1016/j.metabol.2022.155223)
Bailey, C. J. Metformin: historical overview. Diabetologia 60, 1566–1576 (2017). (PMID: 2877608110.1007/s00125-017-4318-z)
Garcia, E. Y. Flumamine, a new synthetic analgesic and anti-flu drug. J. Philipp. Med. Assoc. 26, 287–293 (1950). (PMID: 14779282)
Cummings, T. H., Magagnoli, J., Hardin, J. W. & Sutton, S. S. Patients with obesity and a history of metformin treatment have lower influenza mortality: a retrospective cohort study. Pathogens 11, 270 (2022). (PMID: 35215211887673210.3390/pathogens11020270)
Khunti, K. et al. Prescription of glucose-lowering therapies and risk of COVID-19 mortality in people with type 2 diabetes: a nationwide observational study in England. Lancet Diabetes Endocrinol. 9, 293–303 (2021). (PMID: 33798464800961810.1016/S2213-8587(21)00050-4)
Bramante, C. T. et al. Metformin and risk of mortality in patients hospitalised with COVID-19: a retrospective cohort analysis. Lancet Healthy Longev. 2, e34–e41 (2021). (PMID: 3352177210.1016/S2666-7568(20)30033-7)
Lalau, J. D. et al. Metformin use is associated with a reduced risk of mortality in patients with diabetes hospitalised for COVID-19. Diabetes Metab. 47, 101216 (2021). (PMID: 3330993610.1016/j.diabet.2020.101216)
Flory, J. & Lipska, K. Metformin in 2019. JAMA 321, 1926–1927 (2019). (PMID: 31009043755208310.1001/jama.2019.3805)
Foretz, M., Guigas, B., Bertrand, L., Pollak, M. & Viollet, B. Metformin: from mechanisms of action to therapies. Cell Metab. 20, 953–966 (2014). (PMID: 2545673710.1016/j.cmet.2014.09.018)
Matthews, D. R. et al. Glycaemic durability of an early combination therapy with vildagliptin and metformin versus sequential metformin monotherapy in newly diagnosed type 2 diabetes (VERIFY): a 5-year, multicentre, randomised, double-blind trial. Lancet 394, 1519–1529 (2019). (PMID: 3154229210.1016/S0140-6736(19)32131-2)
Day, E. A. et al. Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss. Nat. Metab. 1, 1202–1208 (2019). (PMID: 3269467310.1038/s42255-019-0146-4)
Coll, A. P. et al. GDF15 mediates the effects of metformin on body weight and energy balance. Nature 578, 444–448 (2020). (PMID: 3187564610.1038/s41586-019-1911-y)
Newman, C. & Dunne, F. P. Metformin for pregnancy and beyond: the pros and cons. Diabet. Med. 39, e14700 (2022). (PMID: 3456908210.1111/dme.14700)
Verma, V. & Mehendale, A. M. A review on the use of metformin in pregnancy and its associated fetal outcomes. Cureus 14, e30039 (2022). (PMID: 363817479637404)
Nguyen, L., Chan, S. Y. & Teo, A. K. K. Metformin from mother to unborn child – are there unwarranted effects? EBioMedicine 35, 394–404 (2018). (PMID: 30166273615670610.1016/j.ebiom.2018.08.047)
Feig, D. S. et al. Outcomes in children of women with type 2 diabetes exposed to metformin versus placebo during pregnancy (MiTy Kids): a 24-month follow-up of the MiTy randomised controlled trial. Lancet Diabetes Endocrinol. 11, 191–202 (2023). (PMID: 3674616010.1016/S2213-8587(23)00004-9)
Wilcock, C. & Bailey, C. J. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica 24, 49–57 (1994). (PMID: 816582110.3109/00498259409043220)
Pentikäinen, P. J., Neuvonen, P. J. & Penttilä, A. Pharmacokinetics of metformin after intravenous and oral administration to man. Eur. J. Clin. Pharmacol. 16, 195–202 (1979). (PMID: 49932010.1007/BF00562061)
Jensen, J. B. et al. [11C]-Labeled metformin distribution in the liver and small intestine using dynamic positron emission tomography in mice demonstrates tissue-specific transporter dependency. Diabetes 65, 1724–1730 (2016). (PMID: 2699306510.2337/db16-0032)
Chan, P., Shao, L., Tomlinson, B., Zhang, Y. & Liu, Z. M. Metformin transporter pharmacogenomics: insights into drug disposition – where are we now? Expert. Opin. Drug. Metab. Toxicol. 14, 1149–1159 (2018). (PMID: 30375241)
Graham, G. G. et al. Clinical pharmacokinetics of metformin. Clin. Pharmacokinet. 50, 81–98 (2011). (PMID: 2124107010.2165/11534750-000000000-00000)
Chandel, N. S. et al. Are metformin doses used in murine cancer models clinically relevant? Cell Metab. 23, 569–570 (2016). (PMID: 2707607010.1016/j.cmet.2016.03.010)
He, L. & Wondisford, F. E. Metformin action: concentrations matter. Cell Metab. 21, 159–162 (2015). (PMID: 2565117010.1016/j.cmet.2015.01.003)
Foretz, M., Guigas, B. & Viollet, B. Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus. Nat. Rev. Endocrinol. 15, 569–589 (2019). (PMID: 3143993410.1038/s41574-019-0242-2)
Dowling, R. J. et al. Metformin pharmacokinetics in mouse tumors: implications for human therapy. Cell Metab. 23, 567–568 (2016). (PMID: 2707606910.1016/j.cmet.2016.03.006)
Quinn, B. J. et al. Inhibition of lung tumorigenesis by metformin is associated with decreased plasma IGF-I and diminished receptor tyrosine kinase signaling. Cancer Prev. Res. 6, 801–810 (2013). (PMID: 10.1158/1940-6207.CAPR-13-0058-T)
Sundelin, E., Jensen, J. B., Jakobsen, S., Gormsen, L. C. & Jessen, N. Metformin biodistribution: a key to mechanisms of action? J. Clin. Endocrinol. Metab. 105, dgaa332 (2020). (PMID: 3248040610.1210/clinem/dgaa332)
Singhal, A. et al. Metformin as adjunct antituberculosis therapy. Sci. Transl. Med. 6, 263ra159 (2014). (PMID: 2541147210.1126/scitranslmed.3009885)
Thakkar, B., Aronis, K. N., Vamvini, M. T., Shields, K. & Mantzoros, C. S. Metformin and sulfonylureas in relation to cancer risk in type II diabetes patients: a meta-analysis using primary data of published studies. Metabolism 62, 922–934 (2013). (PMID: 2341978310.1016/j.metabol.2013.01.014)
Gormsen, L. C. et al. Metformin increases endogenous glucose production in non-diabetic individuals and individuals with recent-onset type 2 diabetes. Diabetologia 62, 1251–1256 (2019). (PMID: 3097685110.1007/s00125-019-4872-7)
McCreight, L. J. et al. Metformin increases fasting glucose clearance and endogenous glucose production in non-diabetic individuals. Diabetologia 63, 444–447 (2020). (PMID: 3175821210.1007/s00125-019-05042-1)
Duca, F. A. et al. Metformin activates a duodenal Ampk-dependent pathway to lower hepatic glucose production in rats. Nat. Med. 21, 506–511 (2015). (PMID: 25849133610480710.1038/nm.3787)
Zhang, E. et al. Intestinal AMPK modulation of microbiota mediates crosstalk with brown fat to control thermogenesis. Nat. Commun. 13, 1135 (2022). (PMID: 35241650889448510.1038/s41467-022-28743-5)
Ma, T. et al. Low-dose metformin targets the lysosomal AMPK pathway through PEN2. Nature 603, 159–165 (2022). (PMID: 35197629889101810.1038/s41586-022-04431-8)
Tobar, N. et al. Metformin acts in the gut and induces gut–liver crosstalk. Proc. Natl Acad. Sci. USA 120, e2211933120 (2023). (PMID: 36656866994289210.1073/pnas.2211933120)
Gormsen, L. C. et al. In vivo imaging of human ¹¹ C-metformin in peripheral organs: dosimetry, biodistribution, and kinetic analyses. J. Nucl. Med. 57, 1920–1926 (2016). (PMID: 2746935910.2967/jnumed.116.177774)
Bailey, C. J., Wilcock, C. & Scarpello, J. H. Metformin and the intestine. Diabetologia 51, 1552–1553 (2008). (PMID: 1852867710.1007/s00125-008-1053-5)
Proctor, W. R. et al. Why does the intestine lack basolateral efflux transporters for cationic compounds? A provocative hypothesis. J. Pharm. Sci. 105, 484–496 (2016). (PMID: 2686941310.1016/j.xphs.2015.11.040)
Shirasaka, Y. et al. Multiple transport mechanisms involved in the intestinal absorption of metformin: impact on the nonlinear absorption kinetics. J. Pharm. Sci. 111, 1531–1541 (2022). (PMID: 3509086510.1016/j.xphs.2022.01.008)
Wilcock, C. & Bailey, C. J. Reconsideration of inhibitory effect of metformin on intestinal glucose absorption. J. Pharm. Pharmacol. 43, 120–121 (1991). (PMID: 167289610.1111/j.2042-7158.1991.tb06645.x)
Ikeda, T., Iwata, K. & Murakami, H. Inhibitory effect of metformin on intestinal glucose absorption in the perfused rat intestine. Biochem. Pharmacol. 59, 887–890 (2000). (PMID: 1071834810.1016/S0006-2952(99)00396-2)
Wu, T. et al. Metformin reduces the rate of small intestinal glucose absorption in type 2 diabetes. Diabetes Obes. Metab. 19, 290–293 (2017). (PMID: 2776198410.1111/dom.12812)
Bailey, C. J. Metformin and intestinal glucose handling. Diabetes Metab. Rev. 11, S23–S32 (1995). (PMID: 852948110.1002/dmr.5610110505)
Zubiaga, L. et al. Oral metformin transiently lowers post-prandial glucose response by reducing the apical expression of sodium-glucose co-transporter 1 in enterocytes. iScience 26, 106057 (2023). (PMID: 369420501002415710.1016/j.isci.2023.106057)
Borg, M. J. et al. Comparative effects of proximal and distal small intestinal administration of metformin on plasma glucose and glucagon-like peptide-1, and gastric emptying after oral glucose, in type 2 diabetes. Diabetes Obes. Metab. 21, 640–647 (2019). (PMID: 3037068610.1111/dom.13567)
Koffert, J. P. et al. Metformin treatment significantly enhances intestinal glucose uptake in patients with type 2 diabetes: results from a randomized clinical trial. Diabetes Res. Clin. Pract. 131, 208–216 (2017). (PMID: 2877804710.1016/j.diabres.2017.07.015)
Chang, H. S., Kim, S. J. & Kim, Y. H. Association between colonic ¹⁸ F-FDG uptake and glycemic control in patients with diabetes mellitus. Nucl. Med. Mol. Imaging 54, 168–174 (2020). (PMID: 32831962742964510.1007/s13139-020-00647-6)
Ito, J. et al. Dose-dependent accumulation of glucose in the intestinal wall and lumen induced by metformin as revealed by ¹⁸ F-labelled fluorodeoxyglucose positron emission tomography-MRI. Diabetes Obes. Metab. 23, 692–699 (2021). (PMID: 3323652310.1111/dom.14262)
Morita, Y. et al. Enhanced release of glucose into the intraluminal space of the intestine associated with metformin treatment as revealed by [ ¹⁸ F]fluorodeoxyglucose PET-MRI. Diabetes Care 43, 1796–1802 (2020). (PMID: 3249375410.2337/dc20-0093)
Horakova, O. et al. Metformin acutely lowers blood glucose levels by inhibition of intestinal glucose transport. Sci. Rep. 9, 6156 (2019). (PMID: 30992489646811910.1038/s41598-019-42531-0)
Ait-Omar, A. et al. GLUT2 accumulation in enterocyte apical and intracellular membranes: a study in morbidly obese human subjects and ob/ob and high fat-fed mice. Diabetes 60, 2598–2607 (2011). (PMID: 21852673317828610.2337/db10-1740)
Rathmann, W. et al. A variant of the glucose transporter gene SLC2A2 modifies the glycaemic response to metformin therapy in recently diagnosed type 2 diabetes. Diabetologia 62, 286–291 (2019). (PMID: 3041382910.1007/s00125-018-4759-z)
McCreight, L. J., Bailey, C. J. & Pearson, E. R. Metformin and the gastrointestinal tract. Diabetologia 59, 426–435 (2016). (PMID: 26780750474250810.1007/s00125-015-3844-9)
Kjøbsted, R. et al. Metformin improves glycemia independently of skeletal muscle AMPK via enhanced intestinal glucose clearance. Preprint at bioRxiv https://www.biorxiv.org/content/10.1101/2022.05.22.492936v1 (2022).
Rittig, N. et al. Metformin stimulates intestinal glycolysis and lactate release: a single-dose study of metformin in patients with intrahepatic portosystemic stent. Clin. Pharmacol. Ther. 110, 1329–1336 (2021). (PMID: 3433131610.1002/cpt.2382)
Schommers, P. et al. Metformin causes a futile intestinal-hepatic cycle which increases energy expenditure and slows down development of a type 2 diabetes-like state. Mol. Metab. 6, 737–747 (2017). (PMID: 28702329548524410.1016/j.molmet.2017.05.002)
Chondronikola, M. et al. Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans. Diabetes 63, 4089–4099 (2014). (PMID: 25056438423800510.2337/db14-0746)
Sponton, C. H. et al. The regulation of glucose and lipid homeostasis via PLTP as a mediator of BAT–liver communication. EMBO Rep. 21, e49828 (2020). (PMID: 32672883750706210.15252/embr.201949828)
Breining, P. et al. Metformin targets brown adipose tissue in vivo and reduces oxygen consumption in vitro. Diabetes Obes. Metab. 20, 2264–2273 (2018). (PMID: 2975275910.1111/dom.13362)
Bridges, H. R. et al. Structural basis of mammalian respiratory complex I inhibition by medicinal biguanides. Science 379, 351–357 (2023). (PMID: 36701435761422710.1126/science.ade3332)
Bridges, H. R., Jones, A. J., Pollak, M. N. & Hirst, J. Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem. J. 462, 475–487 (2014). (PMID: 2501763010.1042/BJ20140620)
Madiraju, A. K. et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510, 542–546 (2014). (PMID: 24847880407424410.1038/nature13270)
LaMoia, T. E. et al. Metformin, phenformin, and galegine inhibit complex IV activity and reduce glycerol-derived gluconeogenesis. Proc. Natl Acad. Sci. USA 119, e2122287119 (2022). (PMID: 35238637891601010.1073/pnas.2122287119)
MacDonald, M. J., Ansari, I. H., Longacre, M. J. & Stoker, S. W. Metformin’s therapeutic efficacy in the treatment of diabetes does not involve inhibition of mitochondrial glycerol phosphate dehydrogenase. Diabetes 70, 1575–1580 (2021). (PMID: 3384999710.2337/db20-1143)
Fontaine, E. Metformin-induced mitochondrial complex I inhibition: facts, uncertainties, and consequences. Front. Endocrinol. 9, 753 (2018). (PMID: 10.3389/fendo.2018.00753)
Pecinová, A., Brázdová, A., Drahota, Z., Houštěk, J. & Mráček, T. Mitochondrial targets of metformin – are they physiologically relevant? Biofactors 45, 703–711 (2019). (PMID: 3134378610.1002/biof.1548)
Vial, G., Detaille, D. & Guigas, B. Role of mitochondria in the mechanism(s) of action of metformin. Front. Endocrinol. 10, 294 (2019). (PMID: 10.3389/fendo.2019.00294)
Zhou, G. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167–1174 (2001). (PMID: 1160262420953310.1172/JCI13505)
Shaw, R. J. et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310, 1642–1646 (2005). (PMID: 16308421307442710.1126/science.1120781)
Zhang, C. S. et al. Metformin activates AMPK through the lysosomal pathway. Cell Metab. 24, 521–522 (2016). (PMID: 2773283110.1016/j.cmet.2016.09.003)
Howell, J. J. et al. Metformin inhibits hepatic mTORC1 signaling via dose-dependent mechanisms involving AMPK and the TSC complex. Cell Metab. 25, 463–471 (2017). (PMID: 28089566529904410.1016/j.cmet.2016.12.009)
Hunter, R. W. et al. Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase. Nat. Med. 24, 1395–1406 (2018). (PMID: 30150719620733810.1038/s41591-018-0159-7)
Miller, R. A. et al. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 494, 256–260 (2013). (PMID: 23292513357321810.1038/nature11808)
Foretz, M. et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J. Clin. Invest. 120, 2355–2369 (2010). (PMID: 20577053289858510.1172/JCI40671)
Olivier, S. et al. Deletion of intestinal epithelial AMP-activated protein kinase alters distal colon permeability but not glucose homeostasis. Mol. Metab. 47, 101183 (2021). (PMID: 33548500792188310.1016/j.molmet.2021.101183)
Fullerton, M. D. et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat. Med. 19, 1649–1654 (2013). (PMID: 24185692496526810.1038/nm.3372)
Stein, B. D. et al. Quantitative in vivo proteomics of metformin response in liver reveals AMPK-dependent and -independent signaling networks. Cell Rep. 29, 3331–3348.e7 (2019). (PMID: 31801093698079210.1016/j.celrep.2019.10.117)
LaMoia, T. E. & Shulman, G. I. Cellular and molecular mechanisms of metformin action. Endocr. Rev. 42, 77–96 (2021). (PMID: 3289738810.1210/endrev/bnaa023)
Yoval-Sánchez, B., Ansari, F., Lange, D. & Galkin, A. Effect of metformin on intact mitochondria from liver and brain: concept revisited. Eur. J. Pharmacol. 931, 175177 (2022). (PMID: 35934089962360410.1016/j.ejphar.2022.175177)
Owen, M. R., Doran, E. & Halestrap, A. P. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J. 348, 607–614 (2000). (PMID: 10839993122110410.1042/bj3480607)
Alshawi, A. & Agius, L. Low metformin causes a more oxidized mitochondrial NADH/NAD redox state in hepatocytes and inhibits gluconeogenesis by a redox-independent mechanism. J. Biol. Chem. 294, 2839–2853 (2019). (PMID: 3059158610.1074/jbc.RA118.006670)
Cao, J. et al. Low concentrations of metformin suppress glucose production in hepatocytes through AMP-activated protein kinase (AMPK). J. Biol. Chem. 289, 20435–20446 (2014). (PMID: 24928508411025510.1074/jbc.M114.567271)
Zhang, C. S. et al. The lysosomal v-ATPase-Ragulator complex is a common activator for AMPK and mTORC1, acting as a switch between catabolism and anabolism. Cell Metab. 20, 526–540 (2014). (PMID: 2500218310.1016/j.cmet.2014.06.014)
Blazina, I. & Selph, S. Diabetes drugs for nonalcoholic fatty liver disease: a systematic review. Syst. Rev. 8, 295 (2019). (PMID: 31783920688475310.1186/s13643-019-1200-8)
Li, Y., Liu, L., Wang, B., Wang, J. & Chen, D. Metformin in non-alcoholic fatty liver disease: a systematic review and meta-analysis. Biomed. Rep. 1, 57–64 (2013). (PMID: 2464889410.3892/br.2012.18)
Holmes, O., Paturi, S., Selkoe, D. J. & Wolfe, M. S. Pen-2 is essential for γ-secretase complex stability and trafficking but partially dispensable for endoproteolysis. Biochemistry 53, 4393–4406 (2014). (PMID: 2494111110.1021/bi500489j)
Hasenour, C. M. et al. 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) effect on glucose production, but not energy metabolism, is independent of hepatic AMPK in vivo. J. Biol. Chem. 289, 5950–5959 (2014). (PMID: 24403081393766310.1074/jbc.M113.528232)
Cokorinos, E. C. et al. Activation of skeletal muscle AMPK promotes glucose disposal and glucose lowering in non-human primates and mice. Cell Metab. 25, 1147–1159.e10 (2017). (PMID: 2846793110.1016/j.cmet.2017.04.010)
Madiraju, A. K. et al. Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo. Nat. Med. 24, 1384–1394 (2018). (PMID: 30038219612919610.1038/s41591-018-0125-4)
Baur, J. A. & Birnbaum, M. J. Control of gluconeogenesis by metformin: does redox trump energy charge? Cell Metab. 20, 197–199 (2014). (PMID: 25100057415496410.1016/j.cmet.2014.07.013)
Saheki, T. et al. Citrin/mitochondrial glycerol-3-phosphate dehydrogenase double knock-out mice recapitulate features of human citrin deficiency. J. Biol. Chem. 282, 25041–25052 (2007). (PMID: 1759177610.1074/jbc.M702031200)
Calza, G. et al. Lactate-induced glucose output is unchanged by metformin at a therapeutic concentration – a mass spectrometry imaging study of the perfused rat liver. Front. Pharmacol. 9, 141 (2018). (PMID: 29520235582741510.3389/fphar.2018.00141)
Glossmann, H. H. & Lutz, O. M. D. Commentary: lactate-induced glucose output is unchanged by metformin at a therapeutic concentration – a mass spectrometry imaging study of the perfused rat liver. Front. Pharmacol. 10, 90 (2019). (PMID: 30837871638978510.3389/fphar.2019.00090)
Logie, L. et al. Cellular responses to the metal-binding properties of metformin. Diabetes 61, 1423–1433 (2012). (PMID: 22492524335726710.2337/db11-0961)
El-Mir, M. Y. et al. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem. 275, 223–228 (2000). (PMID: 1061760810.1074/jbc.275.1.223)
Hawley, S. A. et al. Use of cells expressing γ subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab. 11, 554–565 (2010). (PMID: 20519126293596510.1016/j.cmet.2010.04.001)
Xie, D. et al. Let-7 underlies metformin-induced inhibition of hepatic glucose production. Proc. Natl Acad. Sci. USA 119, e2122217119 (2022). (PMID: 35344434916910810.1073/pnas.2122217119)
Karlsson, F. H. et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 498, 99–103 (2013). (PMID: 2371938010.1038/nature12198)
Napolitano, A. et al. Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PLoS ONE 9, e100778 (2014). (PMID: 24988476407965710.1371/journal.pone.0100778)
Forslund, K. et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528, 262–266 (2015). (PMID: 26633628468109910.1038/nature15766)
de la Cuesta-Zuluaga, J. et al. Metformin is associated with higher relative abundance of mucin-degrading Akkermansia muciniphila and several short-chain fatty acid-producing microbiota in the gut. Diabetes Care 40, 54–62 (2017). (PMID: 2799900210.2337/dc16-1324)
Wu, H. et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat. Med. 23, 850–858 (2017). (PMID: 2853070210.1038/nm.4345)
Vich Vila, A. et al. Impact of commonly used drugs on the composition and metabolic function of the gut microbiota. Nat. Commun. 11, 362 (2020). (PMID: 31953381696917010.1038/s41467-019-14177-z)
Mueller, N. T. et al. Metformin affects gut microbiome composition and function and circulating short-chain fatty acids: a randomized trial. Diabetes Care 44, 1462–1471 (2021). (PMID: 34006565832318510.2337/dc20-2257)
Zhang, Q. & Hu, N. Effects of metformin on the gut microbiota in obesity and type 2 diabetes mellitus. Diabetes Metab. Syndr. Obes. 13, 5003–5014 (2020). (PMID: 33364804775159510.2147/DMSO.S286430)
Alvarez-Silva, C. et al. Trans-ethnic gut microbiota signatures of type 2 diabetes in Denmark and India. Genome Med. 13, 37 (2021). (PMID: 33658058793154210.1186/s13073-021-00856-4)
Elbere, I. et al. Association of metformin administration with gut microbiome dysbiosis in healthy volunteers. PLoS ONE 13, e0204317 (2018). (PMID: 30261008616008510.1371/journal.pone.0204317)
Bryrup, T. et al. Metformin-induced changes of the gut microbiota in healthy young men: results of a non-blinded, one-armed intervention study. Diabetologia 62, 1024–1035 (2019). (PMID: 30904939650909210.1007/s00125-019-4848-7)
Yang, Y. et al. Changes of saliva microbiota in the onset and after the treatment of diabetes in patients with periodontitis. Aging 12, 13090–13114 (2020). (PMID: 32634783737787610.18632/aging.103399)
Lee, H. & Ko, G. Effect of metformin on metabolic improvement and gut microbiota. Appl. Env. Microbiol. 80, 5935–5943 (2014). (PMID: 10.1128/AEM.01357-14)
Shin, N. R. et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 63, 727–735 (2014). (PMID: 2380456110.1136/gutjnl-2012-303839)
Bauer, P. V. et al. Metformin alters upper small intestinal microbiota that impact a glucose-SGLT1-sensing glucoregulatory pathway. Cell Metab. 27, 101–117 (2018). (PMID: 2905651310.1016/j.cmet.2017.09.019)
Zhang, X. et al. Modulation of gut microbiota by berberine and metformin during the treatment of high-fat diet-induced obesity in rats. Sci. Rep. 5, 14405 (2015). (PMID: 26396057458577610.1038/srep14405)
Silamiķele, L. et al. Metformin strongly affects gut microbiome composition in high-fat diet-induced type 2 diabetes mouse model of both sexes. Front. Endocrinol. 12, 626359 (2021). (PMID: 10.3389/fendo.2021.626359)
Broadfield, L. A. et al. Metformin-induced reductions in tumor growth involves modulation of the gut microbiome. Mol. Metab. 61, 101498 (2022). (PMID: 35452877909666910.1016/j.molmet.2022.101498)
Adeshirlarijaney, A., Zou, J., Tran, H. Q., Chassaing, B. & Gewirtz, A. T. Amelioration of metabolic syndrome by metformin associates with reduced indices of low-grade inflammation independently of the gut microbiota. Am. J. Physiol. Endocrinol. Metab. 317, E1121–E1130 (2019). (PMID: 31573841696250510.1152/ajpendo.00245.2019)
Adeshirlarijaney, A. & Gewirtz, A. T. Considering gut microbiota in treatment of type 2 diabetes mellitus. Gut Microbes 11, 253–264 (2020). (PMID: 32005089752429110.1080/19490976.2020.1717719)
Bravard, A. et al. Metformin treatment for 8 days impacts multiple intestinal parameters in high-fat high-sucrose fed mice. Sci. Rep. 11, 16684 (2021). (PMID: 34404817837111010.1038/s41598-021-95117-0)
Sun, L. et al. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nat. Med. 24, 1919–1929 (2018). (PMID: 30397356647922610.1038/s41591-018-0222-4)
DeFronzo, R. A. et al. Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials. Diabetologia 59, 1645–1654 (2016). (PMID: 27216492493048510.1007/s00125-016-3992-6)
Ke, H. et al. Metformin exerts anti-inflammatory and mucus barrier protective effects by enriching Akkermansia muciniphila in mice with ulcerative colitis. Front. Pharmacol. 12, 726707 (2021). (PMID: 34658866851472410.3389/fphar.2021.726707)
Zhou, Z. Y. et al. Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling. Acta Pharmacol. Sin. 37, 1063–1075 (2016). (PMID: 27180982497337710.1038/aps.2016.21)
Ahmadi, S. et al. Metformin reduces aging-related leaky gut and improves cognitive function by beneficially modulating gut microbiome/goblet cell/mucin axis. J. Gerontol. A Biol. Sci. Med. Sci. 75, e9–e21 (2020). (PMID: 32129462730218210.1093/gerona/glaa056)
Brandt, A. et al. Metformin attenuates the onset of non-alcoholic fatty liver disease and affects intestinal microbiota and barrier in small intestine. Sci. Rep. 9, 6668 (2019). (PMID: 31040374649148310.1038/s41598-019-43228-0)
Li, L. et al. An in vitro model maintaining taxon-specific functional activities of the gut microbiome. Nat. Commun. 10, 4146 (2019). (PMID: 31515476674263910.1038/s41467-019-12087-8)
Hao, Z. et al. Metaproteomics reveals growth phase-dependent responses of an in vitro gut microbiota to metformin. J. Am. Soc. Mass. Spectrom. 31, 1448–1458 (2020). (PMID: 3232060710.1021/jasms.0c00054)
Rosario, D. et al. Understanding the representative gut microbiota dysbiosis in metformin-treated type 2 diabetes patients using genome-scale metabolic modeling. Front. Physiol. 9, 775 (2018). (PMID: 29988585602667610.3389/fphys.2018.00775)
Cabreiro, F. et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell 153, 228–239 (2013). (PMID: 23540700389846810.1016/j.cell.2013.02.035)
Pryor, R. et al. Host-microbe-drug-nutrient screen identifies bacterial effectors of metformin therapy. Cell 178, 1299–1312.e29 (2019). (PMID: 31474368673677810.1016/j.cell.2019.08.003)
Lee, Y. et al. Changes in the gut microbiome influence the hypoglycemic effect of metformin through the altered metabolism of branched-chain and nonessential amino acids. Diabetes Res. Clin. Pract. 178, 108985 (2021). (PMID: 3432969210.1016/j.diabres.2021.108985)
Hung, W. W. et al. Gut microbiota compositions and metabolic functions in type 2 diabetes differ with glycemic durability to metformin monotherapy. Diabetes Res. Clin. Pract. 174, 108731 (2021). (PMID: 3367699510.1016/j.diabres.2021.108731)
De Vadder, F. et al. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 156, 84–96 (2014). (PMID: 2441265110.1016/j.cell.2013.12.016)
Holst, J. J., Gasbjerg, L. S. & Rosenkilde, M. M. The role of incretins on insulin function and glucose homeostasis. Endocrinology 162, bqab065 (2021). (PMID: 33782700816894310.1210/endocr/bqab065)
Sansome, D. J. et al. Mechanism of glucose-lowering by metformin in type 2 diabetes: role of bile acids. Diabetes Obes. Metab. 22, 141–148 (2020). (PMID: 3146864210.1111/dom.13869)
Zhernakova, A. et al. Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science 352, 565–569 (2016). (PMID: 27126040524084410.1126/science.aad3369)
Su, C. et al. Metformin alleviates choline diet-induced TMAO elevation in C57BL/6J mice by influencing gut-microbiota composition and functionality. Nutr. Diabetes 11, 27 (2021). (PMID: 34389700836362410.1038/s41387-021-00169-w)
Kuka, J. et al. Metformin decreases bacterial trimethylamine production and trimethylamine N-oxide levels in db/db mice. Sci. Rep. 10, 14555 (2020). (PMID: 32884086747127610.1038/s41598-020-71470-4)
Ji, S., Wang, L. & Li, L. Effect of metformin on short-term high-fat diet-induced weight gain and anxiety-like behavior and the gut microbiota. Front. Endocrinol. 10, 704 (2019). (PMID: 10.3389/fendo.2019.00704)
Deng, W. et al. Metformin alleviates autistic-like behaviors elicited by high-fat diet consumption and modulates the crosstalk between serotonin and gut microbiota in mice. Behav. Neurol. 2022, 6711160 (2022). (PMID: 35222739887265310.1155/2022/6711160)
Huang, X. et al. Metformin elicits antitumour effect by modulation of the gut microbiota and rescues Fusobacterium nucleatum-induced colorectal tumourigenesis. EBioMedicine 61, 103037 (2020). (PMID: 33039709755323910.1016/j.ebiom.2020.103037)
Wanchaitanawong, W., Thinrungroj, N., Chattipakorn, S. C., Chattipakorn, N. & Shinlapawittayatorn, K. Repurposing metformin as a potential treatment for inflammatory bowel disease: evidence from cell to the clinic. Int. Immunopharmacol. 112, 109230 (2022). (PMID: 3609978610.1016/j.intimp.2022.109230)
Liu, Z. et al. Metformin affects gut microbiota composition and diversity associated with amelioration of dextran sulfate sodium-induced colitis in mice. Front. Pharmacol. 12, 640347 (2021). (PMID: 34122067819163410.3389/fphar.2021.640347)
Seicaru, E. M., Popa Ilie, I. R., Cătinean, A., Crăciun, A. M. & Ghervan, C. Enhancing metformin effects by adding gut microbiota modulators to ameliorate the metabolic status of obese, insulin-resistant hosts. J. Gastrointestin Liver Dis. 31, 344–354 (2022). (PMID: 3611270510.15403/jgld-4248)
Koh, A. et al. Microbial imidazole propionate affects responses to metformin through p38γ-dependent inhibitory AMPK phosphorylation. Cell Metab. 32, 643–653 (2020). (PMID: 32783890754603410.1016/j.cmet.2020.07.012)
Bonnet, F. & Scheen, A. Understanding and overcoming metformin gastrointestinal intolerance. Diabetes Obes. Metab. 19, 473–481 (2017). (PMID: 2798724810.1111/dom.12854)
Díaz-Perdigones, C. M., Muñoz-Garach, A., Álvarez-Bermúdez, M. D., Moreno-Indias, I. & Tinahones, F. J. Gut microbiota of patients with type 2 diabetes and gastrointestinal intolerance to metformin differs in composition and functionality from tolerant patients. Biomed. Pharmacother. 145, 112448 (2022). (PMID: 3484410410.1016/j.biopha.2021.112448)
Nakajima, H. et al. The effects of metformin on the gut microbiota of patients with type 2 diabetes: a two-center, quasi-experimental study. Life 10, 195 (2020). (PMID: 32932871755598610.3390/life10090195)
Hotamisligil, G. S. Inflammation, metaflammation and immunometabolic disorders. Nature 542, 177–185 (2017). (PMID: 2817965610.1038/nature21363)
Lee, Y. S., Wollam, J. & Olefsky, J. M. An integrated view of immunometabolism. Cell 172, 22–40 (2018). (PMID: 29328913845172310.1016/j.cell.2017.12.025)
Rohm, T. V., Meier, D. T., Olefsky, J. M. & Donath, M. Y. Inflammation in obesity, diabetes, and related disorders. Immunity 55, 31–55 (2022). (PMID: 35021057877345710.1016/j.immuni.2021.12.013)
Hoogerland, J. A., Staels, B. & Dombrowicz, D. Immune-metabolic interactions in homeostasis and the progression to NASH. Trends Endocrinol. Metab. 33, 690–709 (2022). (PMID: 3596191310.1016/j.tem.2022.07.001)
Roy, P., Orecchioni, M. & Ley, K. How the immune system shapes atherosclerosis: roles of innate and adaptive immunity. Nat. Rev. Immunol. 22, 251–265 (2022). (PMID: 3438984110.1038/s41577-021-00584-1)
Eckold, C. et al. Impact of intermediate hyperglycemia and diabetes on immune dysfunction in tuberculosis. Clin. Infect. Dis. 72, 69–78 (2021). (PMID: 3253383210.1093/cid/ciaa751)
Caputa, G., Castoldi, A. & Pearce, E. J. Metabolic adaptations of tissue-resident immune cells. Nat. Immunol. 20, 793–801 (2019). (PMID: 3121371510.1038/s41590-019-0407-0)
Kristófi, R. & Eriksson, J. W. Metformin as an anti-inflammatory agent: a short review. J. Endocrinol. 251, R11–R22 (2021). (PMID: 3446329210.1530/JOE-21-0194)
Bhansali, S., Bhansali, A. & Dhawan, V. Metformin promotes mitophagy in mononuclear cells: a potential in vitro model for unraveling metformin’s mechanism of action. Ann. N. Y. Acad. Sci. 1463, 23–36 (2020). (PMID: 3122564910.1111/nyas.14141)
de Marañón, A. M. et al. Metformin modulates mitochondrial function and mitophagy in peripheral blood mononuclear cells from type 2 diabetic patients. Redox Biol. 53, 102342 (2022). (PMID: 35605453912471310.1016/j.redox.2022.102342)
Menegazzo, L. et al. The antidiabetic drug metformin blunts NETosis in vitro and reduces circulating NETosis biomarkers in vivo. Acta Diabetol. 55, 593–601 (2018). (PMID: 2954657910.1007/s00592-018-1129-8)
Wang, H., Li, T., Chen, S., Gu, Y. & Ye, S. Neutrophil extracellular trap mitochondrial DNA and its autoantibody in systemic lupus erythematosus and a proof-of-concept trial of metformin. Arthritis Rheumatol. 67, 3190–3200 (2015). (PMID: 2624580210.1002/art.39296)
Wculek, S. K., Dunphy, G., Heras-Murillo, I., Mastrangelo, A. & Sancho, D. Metabolism of tissue macrophages in homeostasis and pathology. Cell Mol. Immunol. 19, 384–408 (2022). (PMID: 3487670410.1038/s41423-021-00791-9)
Xiong, W. et al. Metformin alleviates inflammation through suppressing FASN-dependent palmitoylation of Akt. Cell Death Dis. 12, 934 (2021). (PMID: 34642298851102510.1038/s41419-021-04235-0)
Xian, H. et al. Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation. Immunity 54, 1463–1477 (2021). (PMID: 34115964818976510.1016/j.immuni.2021.05.004)
Soberanes, S. et al. Metformin targets mitochondrial electron transport to reduce air-pollution-induced thrombosis. Cell Metab. 29, 335–347 (2019). (PMID: 3031833910.1016/j.cmet.2018.09.019)
Franceschi, C., Garagnani, P., Parini, P., Giuliani, C. & Santoro, A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat. Rev. Endocrinol. 14, 576–590 (2018). (PMID: 3004614810.1038/s41574-018-0059-4)
Aiello, A. et al. Immunosenescence and its hallmarks: how to oppose aging strategically? A review of potential options for therapeutic intervention. Front. Immunol. 10, 2247 (2019). (PMID: 31608061677382510.3389/fimmu.2019.02247)
Kulkarni, A. S., Gubbi, S. & Barzilai, N. Benefits of metformin in attenuating the hallmarks of aging. Cell Metab. 32, 15–30 (2020). (PMID: 32333835734742610.1016/j.cmet.2020.04.001)
Frasca, D., Diaz, A., Romero, M. & Blomberg, B. B. Metformin enhances B cell function and antibody responses of elderly individuals with type-2 diabetes mellitus. Front. Aging 2, 715981 (2021). (PMID: 35822013926139210.3389/fragi.2021.715981)
Lee, J. Y. et al. Diabetes mellitus and ovarian cancer risk: a systematic review and meta-analysis of observational studies. Int. J. Gynecol. Cancer 23, 402–412 (2013). (PMID: 2335437110.1097/IGC.0b013e31828189b2)
Landry, D. A. et al. Metformin prevents age-associated ovarian fibrosis by modulating the immune landscape in female mice. Sci. Adv. 8, eabq1475 (2022). (PMID: 3605435610.1126/sciadv.abq1475)
Bharath, L. P. et al. Metformin enhances autophagy and normalizes mitochondrial function to alleviate aging-associated inflammation. Cell Metab. 32, 44–55 (2020). (PMID: 32402267721713310.1016/j.cmet.2020.04.015)
Ursini, F. et al. Metformin and autoimmunity: a “new deal” of an old drug. Front. Immunol. 9, 1236 (2018). (PMID: 29915588599490910.3389/fimmu.2018.01236)
Titov, A. A., Baker, H. V., Brusko, T. M., Sobel, E. S. & Morel, L. Metformin inhibits the type 1 IFN response in human CD4 ⁺ T cells. J. Immunol. 203, 338–348 (2019). (PMID: 3116053410.4049/jimmunol.1801651)
Duan, W. et al. Metformin mitigates autoimmune insulitis by inhibiting Th1 and Th17 responses while promoting Treg production. Am. J. Transl. Res. 11, 2393–2402 (2019). (PMID: 311058456511786)
Sun, F. et al. Safety and efficacy of metformin in systemic lupus erythematosus: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Rheumatol. 2, e210–e216 (2020). (PMID: 10.1016/S2665-9913(20)30004-7)
Malik, F. et al. Is metformin poised for a second career as an antimicrobial? Diabetes Metab. Res. Rev. 34, e2975 (2018). (PMID: 2927156310.1002/dmrr.2975)
Kim, K., Yang, W. H., Jung, Y. S. & Cha, J. H. A new aspect of an old friend: the beneficial effect of metformin on anti-tumor immunity. BMB Rep. 53, 512–520 (2020). (PMID: 32731915760714910.5483/BMBRep.2020.53.10.149)
Leow, M. K. et al. Latent tuberculosis in patients with diabetes mellitus: prevalence, progression and public health implications. Exp. Clin. Endocrinol. Diabetes 122, 528–532 (2014). (PMID: 2500336210.1055/s-0034-1377044)
Lachmandas, E. et al. Metformin alters human host responses to Mycobacterium tuberculosis in healthy subjects. J. Infect. Dis. 220, 139–150 (2019). (PMID: 30753544654889710.1093/infdis/jiz064)
Böhme, J. et al. Metformin enhances anti-mycobacterial responses by educating CD8 ⁺ T-cell immunometabolic circuits. Nat. Commun. 11, 5225 (2020). (PMID: 33067434756785610.1038/s41467-020-19095-z)
Wang, S. et al. Low-dose metformin reprograms the tumor immune microenvironment in human esophageal cancer: results of a phase II clinical trial. Clin. Cancer Res. 26, 4921–4932 (2020). (PMID: 3264692210.1158/1078-0432.CCR-20-0113)
Crist, M. et al. Metformin increases natural killer cell functions in head and neck squamous cell carcinoma through CXCL1 inhibition. J. Immunother. Cancer 10, e005632 (2022). (PMID: 36328378963914610.1136/jitc-2022-005632)
Wabitsch, S. et al. Metformin treatment rescues CD8 ⁺ T-cell response to immune checkpoint inhibitor therapy in mice with NAFLD. J. Hepatol. 77, 748–760 (2022). (PMID: 3537817210.1016/j.jhep.2022.03.010)
Wei, Z. et al. Boosting anti-PD-1 therapy with metformin-loaded macrophage-derived microparticles. Nat. Commun. 12, 440 (2021). (PMID: 33469052781573010.1038/s41467-020-20723-x)
Evans, J. M., Donnelly, L. A., Emslie-Smith, A. M., Alessi, D. R. & Morris, A. D. Metformin and reduced risk of cancer in diabetic patients. BMJ 330, 1304–1305 (2005). (PMID: 1584920655820510.1136/bmj.38415.708634.F7)
Heckman-Stoddard, B. M., DeCensi, A., Sahasrabuddhe, V. V. & Ford, L. G. Repurposing metformin for the prevention of cancer and cancer recurrence. Diabetologia 60, 1639–1647 (2017). (PMID: 28776080570914710.1007/s00125-017-4372-6)
Misirkic Marjanovic, M. S., Vucicevic, L. M., Despotovic, A. R., Stamenkovic, M. M. & Janjetovic, K. D. Dual anticancer role of metformin: an old drug regulating AMPK dependent/independent pathways in metabolic, oncogenic/tumorsuppresing and immunity context. Am. J. Cancer Res. 11, 5625–5643 (2021). (PMID: 348734848640802)
Badrick, E. & Renehan, A. G. Diabetes and cancer: 5 years into the recent controversy. Eur. J. Cancer 50, 2119–2125 (2014). (PMID: 2493006010.1016/j.ejca.2014.04.032)
Goodwin, P. J. et al. Effect of metformin vs placebo on invasive disease-free survival in patients with breast cancer: the MA.32 randomized clinical trial. JAMA 327, 1963–1973 (2022). (PMID: 35608580913174510.1001/jama.2022.6147)
Skuli, S. J. et al. Metformin and cancer, an ambiguanidous relationship. Pharmaceuticals 15, 626 (2022). (PMID: 35631452914450710.3390/ph15050626)
Heng, T. S. & Painter, M. W. The Immunological Genome Project: networks of gene expression in immune cells. Nat. Immunol. 9, 1091–1094 (2008). (PMID: 1880015710.1038/ni1008-1091)
Jones, R. C. et al. The Tabula Sapiens: a multiple-organ, single-cell transcriptomic atlas of humans. Science 376, eabl4896 (2022). (PMID: 3554940410.1126/science.abl4896)
Vara-Ciruelos, D. et al. Phenformin, but not metformin, delays development of T cell acute lymphoblastic leukemia/lymphoma via cell-autonomous AMPK activation. Cell Rep. 27, 690–698.e4 (2019). (PMID: 30995468648477610.1016/j.celrep.2019.03.067)
Zhao, H., Swanson, K. D. & Zheng, B. Therapeutic repurposing of biguanides in cancer. Trends Cancer 7, 714–730 (2021). (PMID: 33865798829519410.1016/j.trecan.2021.03.001)
Valencia, W. M., Palacio, A., Tamariz, L. & Florez, H. Metformin and ageing: improving ageing outcomes beyond glycaemic control. Diabetologia 60, 1630–1638 (2017). (PMID: 28770328570920910.1007/s00125-017-4349-5)
Anisimov, V. N. et al. If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice. Aging 3, 148–157 (2011). (PMID: 21386129308200910.18632/aging.100273)
Espada, L. et al. Loss of metabolic plasticity underlies metformin toxicity in aged Caenorhabditis elegans. Nat. Metab. 2, 1316–1331 (2020). (PMID: 3313996010.1038/s42255-020-00307-1)
Mohammed, I., Hollenberg, M. D., Ding, H. & Triggle, C. R. A critical review of the evidence that metformin is a putative anti-aging drug that enhances healthspan and extends lifespan. Front. Endocrinol. 12, 718942 (2021). (PMID: 10.3389/fendo.2021.718942)
Simonnet, A. et al. High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation. Obesity 28, 1195–1199 (2020). (PMID: 3227199310.1002/oby.22831)
Petrilli, C. M. et al. Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York city: prospective cohort study. BMJ 369, m1966 (2020). (PMID: 32444366724380110.1136/bmj.m1966)
Cai, Q. et al. Obesity and COVID-19 severity in a designated hospital in Shenzhen, China. Diabetes Care 43, 1392–1398 (2020). (PMID: 3240950210.2337/dc20-0576)
Zhu, L. et al. Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing type 2 diabetes. Cell Metab. 31, 1068–1077 (2020). (PMID: 32369736725216810.1016/j.cmet.2020.04.021)
Stefan, N., Birkenfeld, A. L. & Schulze, M. B. Global pandemics interconnected – obesity, impaired metabolic health and COVID-19. Nat. Rev. Endocrinol. 17, 135–149 (2021). (PMID: 3347953810.1038/s41574-020-00462-1)
Cheng, X. et al. Metformin is associated with higher incidence of acidosis, but not mortality, in individuals with COVID-19 and pre-existing type 2 diabetes. Cell Metab. 32, 537–547.e3 (2020). (PMID: 32861268743998610.1016/j.cmet.2020.08.013)
Gordon, D. E. et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 583, 459–468 (2020). (PMID: 32353859743103010.1038/s41586-020-2286-9)
Schaller, M. A. et al. Ex vivo SARS-CoV-2 infection of human lung reveals heterogeneous host defense and therapeutic responses. JCI Insight 6, e148003 (2021). (PMID: 34357881849230110.1172/jci.insight.148003)
Cory, T. J., Emmons, R. S., Yarbro, J. R., Davis, K. L. & Pence, B. D. Metformin suppresses monocyte immunometabolic activation by SARS-CoV-2 spike protein subunit 1. Front. Immunol. 12, 733921 (2021). (PMID: 34858397863196710.3389/fimmu.2021.733921)
Reis, G. et al. Effect of early treatment with metformin on risk of emergency care and hospitalization among patients with COVID-19: the TOGETHER randomized platform clinical trial. Lancet Reg. Health Am. 6, 100142 (2022). (PMID: 34927127)
Bramante, C. T. et al. Randomized trial of metformin, ivermectin, and fluvoxamine for Covid-19. N. Engl. J. Med. 387, 599–610 (2022). (PMID: 36070710994592210.1056/NEJMoa2201662)
Bramante, C. T. et al. Outpatient treatment of Covid-19 with metformin, ivermectin, and fluvoxamine and the development of Long Covid over 10-month follow-up. Preprint at medRxiv https://www.medrxiv.org/content/10.1101/2022.12.21.22283753v1 (2022).
Gerstein, H. C. et al. Growth differentiation factor 15 as a novel biomarker for metformin. Diabetes Care 40, 280–283 (2017). (PMID: 2797434510.2337/dc16-1682)
Natali, A. et al. Metformin is the key factor in elevated plasma growth differentiation factor-15 levels in type 2 diabetes: a nested, case-control study. Diabetes Obes. Metab. 21, 412–416 (2019). (PMID: 3017854510.1111/dom.13519)
Klein, A. B. et al. The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. Cell Rep. 40, 111258 (2022). (PMID: 3600195610.1016/j.celrep.2022.111258)
Aguilar-Recarte, D. et al. A positive feedback loop between AMPK and GDF15 promotes metformin antidiabetic effects. Pharmacol. Res. 187, 106578 (2022). (PMID: 3643527110.1016/j.phrs.2022.106578)
Klein, A. B., Kleinert, M., Richter, E. A. & Clemmensen, C. GDF15 in appetite and exercise: essential player or coincidental bystander? Endocrinology 163, bqab242 (2022). (PMID: 3484970910.1210/endocr/bqab242)
Yang, L. et al. GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. Nat. Med. 23, 1158–1166 (2017). (PMID: 2884609910.1038/nm.4394)
Mullican, S. E. et al. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat. Med. 23, 1150–1157 (2017). (PMID: 2884609710.1038/nm.4392)
Diabetes Prevention Program Research Group. Long-term safety, tolerability, and weight loss associated with metformin in the Diabetes Prevention Program Outcomes Study. Diabetes Care 35, 731–737 (2012). (PMID: 10.2337/dc11-1299)
Ning, H. H. et al. The effects of metformin on simple obesity: a meta-analysis. Endocrine 62, 528–534 (2018). (PMID: 3015173510.1007/s12020-018-1717-y)
Gao, F. et al. Growth differentiation factor 15 is not associated with glycemic control in patients with type 2 diabetes mellitus treated with metformin: a post-hoc analysis of AIM study. BMC Endocr. Disord. 22, 256 (2022). (PMID: 36273168958820210.1186/s12902-022-01176-3)
Al-Kuraishy, H. M. et al. Metformin and growth differentiation factor 15 (GDF15) in type 2 diabetes mellitus: a hidden treasure. J. Diabetes 14, 806–814 (2022). (PMID: 36444166978939510.1111/1753-0407.13334)
Kincaid, J. W. R. & Coll, A. P. Metformin and GDF15: where are we now? Nat. Rev. Endocrinol. 19, 6–7 (2022). (PMID: 10.1038/s41574-022-00764-6)
Karise, I., Bargut, T. C., Del Sol, M., Aguila, M. B. & Mandarim-de-Lacerda, C. A. Metformin enhances mitochondrial biogenesis and thermogenesis in brown adipocytes of mice. Biomed. Pharmacother. 111, 1156–1165 (2019). (PMID: 3084142910.1016/j.biopha.2019.01.021)
Yang, Q. et al. AMPK/α-ketoglutarate axis dynamically mediates DNA demethylation in the Prdm16 promoter and brown adipogenesis. Cell Metab. 24, 542–554 (2016). (PMID: 27641099506163310.1016/j.cmet.2016.08.010)
Geerling, J. J. et al. Metformin lowers plasma triglycerides by promoting VLDL-triglyceride clearance by brown adipose tissue in mice. Diabetes 63, 880–891 (2014). (PMID: 2427098410.2337/db13-0194)
Tokubuchi, I. et al. Beneficial effects of metformin on energy metabolism and visceral fat volume through a possible mechanism of fatty acid oxidation in human subjects and rats. PLoS ONE 12, e0171293 (2017). (PMID: 28158227529144110.1371/journal.pone.0171293)
English, P. J. et al. Metformin prolongs the postprandial fall in plasma ghrelin concentrations in type 2 diabetes. Diabetes Metab. Res. Rev. 23, 299–303 (2007). (PMID: 1695219910.1002/dmrr.681)
Rouru, J., Isaksson, K., Santti, E., Huupponen, R. & Koulu, M. Metformin and brown adipose tissue thermogenetic activity in genetically obese Zucker rats. Eur. J. Pharmacol. 246, 67–71 (1993). (PMID: 835434310.1016/0922-4106(93)90011-W)
Pescador, N. et al. Metformin reduces macrophage HIF1α-dependent proinflammatory signaling to restore brown adipocyte function in vitro. Redox Biol. 48, 102171 (2021). (PMID: 34736121857748210.1016/j.redox.2021.102171)
Yang, D. et al. A nationwide wastewater-based assessment of metformin consumption across Australia. Env. Int. 165, 107282 (2022). (PMID: 10.1016/j.envint.2022.107282)
He, Y., Zhang, Y. & Ju, F. Metformin contamination in global waters: biotic and abiotic transformation, byproduct generation and toxicity, and evaluation as a pharmaceutical indicator. Env. Sci. Technol. 56, 13528–13545 (2022). (PMID: 10.1021/acs.est.2c02495)
Elizalde-Velázquez, G. A. & Gómez-Oliván, L. M. Occurrence, toxic effects and removal of metformin in the aquatic environments in the world: recent trends and perspectives. Sci. Total. Environ. 702, 134924 (2020). (PMID: 3172634610.1016/j.scitotenv.2019.134924)
Balakrishnan, A., Sillanpää, M., Jacob, M. M. & Vo, D. N. Metformin as an emerging concern in wastewater: occurrence, analysis and treatment methods. Environ. Res. 213, 113613 (2022). (PMID: 3569708310.1016/j.envres.2022.113613)
Ambrosio-Albuquerque, E. P. et al. Metformin environmental exposure: a systematic review. Environ. Toxicol. Pharmacol. 83, 103588 (2021). (PMID: 3346080310.1016/j.etap.2021.103588)
Wilkinson, J. L. et al. Pharmaceutical pollution of the world’s rivers. Proc. Natl Acad. Sci. USA 119, e2113947119 (2022). (PMID: 35165193887271710.1073/pnas.2113947119)
Niemuth, N. J. & Klaper, R. D. Low-dose metformin exposure causes changes in expression of endocrine disruption-associated genes. Aquat. Toxicol. 195, 33–40 (2018). (PMID: 2924876110.1016/j.aquatox.2017.12.003)
Barros, S. et al. Metformin disrupts Danio rerio metabolism at environmentally relevant concentrations: a full life-cycle study. Sci. Total Environ. 846, 157361 (2022). (PMID: 3584332410.1016/j.scitotenv.2022.157361)
Phillips, J. et al. Developmental phenotypic and transcriptomic effects of exposure to nanomolar levels of metformin in zebrafish. Environ. Toxicol. Pharmacol. 87, 103716 (2021). (PMID: 34311114844632010.1016/j.etap.2021.103716)
Barros, S. et al. Are fish populations at risk? Metformin disrupts zebrafish development and reproductive processes at chronic environmentally relevant concentrations. Env. Sci. Technol. 57, 1049–1059 (2023). (PMID: 10.1021/acs.est.2c05719)
Li, T., Xu, Z. J. & Zhou, N. Y. Aerobic degradation of the antidiabetic drug metformin by Aminobacter sp. strain NyZ550. Environ. Sci. Technol. 57, 1510–1519 (2023). (PMID: 10.1021/acs.est.2c07669)

9100L32L2N (Metformin)
0 (Hypoglycemic Agents)
IY9XDZ35W2 (Glucose)

Date Created: 20230502 Date Completed: 20230714 Latest Revision: 20230718

20240628

PMC10153049

10.1038/s41574-023-00833-4

37130947