Metformin: update on mechanisms of action and repurposing potential.
Journal
Nature reviews. Endocrinology
ISSN: 1759-5037
Titre abrégé: Nat Rev Endocrinol
Pays: England
ID NLM: 101500078
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
accepted:
24
03
2023
medline:
14
7
2023
pubmed:
3
5
2023
entrez:
2
5
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37130947
doi: 10.1038/s41574-023-00833-4
pii: 10.1038/s41574-023-00833-4
pmc: PMC10153049
doi:
Substances chimiques
Metformin
9100L32L2N
Hypoglycemic Agents
0
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Review
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
460-476Informations de copyright
© 2023. Springer Nature Limited.
Références
Schernthaner, G. & Schernthaner, G. H. The right place for metformin today. Diabetes Res. Clin. Pract. 159, 107946 (2020).
pubmed: 31778746
doi: 10.1016/j.diabres.2019.107946
Ahmad, E. et al. Where does metformin stand in modern day management of type 2 diabetes? Pharmaceuticals 13, 427 (2020).
pubmed: 33261058
pmcid: 7761522
doi: 10.3390/ph13120427
Triggle, C. R. et al. Metformin: Is it a drug for all reasons and diseases? Metabolism 133, 155223 (2022).
pubmed: 35640743
doi: 10.1016/j.metabol.2022.155223
Bailey, C. J. Metformin: historical overview. Diabetologia 60, 1566–1576 (2017).
pubmed: 28776081
doi: 10.1007/s00125-017-4318-z
Garcia, E. Y. Flumamine, a new synthetic analgesic and anti-flu drug. J. Philipp. Med. Assoc. 26, 287–293 (1950).
pubmed: 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).
pubmed: 35215211
pmcid: 8876732
doi: 10.3390/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).
pubmed: 33798464
pmcid: 8009618
doi: 10.1016/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).
pubmed: 33521772
doi: 10.1016/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).
pubmed: 33309936
doi: 10.1016/j.diabet.2020.101216
Flory, J. & Lipska, K. Metformin in 2019. JAMA 321, 1926–1927 (2019).
pubmed: 31009043
pmcid: 7552083
doi: 10.1001/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).
pubmed: 25456737
doi: 10.1016/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).
pubmed: 31542292
doi: 10.1016/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).
pubmed: 32694673
doi: 10.1038/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).
pubmed: 31875646
doi: 10.1038/s41586-019-1911-y
Newman, C. & Dunne, F. P. Metformin for pregnancy and beyond: the pros and cons. Diabet. Med. 39, e14700 (2022).
pubmed: 34569082
doi: 10.1111/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).
pubmed: 36381747
pmcid: 9637404
Nguyen, L., Chan, S. Y. & Teo, A. K. K. Metformin from mother to unborn child – are there unwarranted effects? EBioMedicine 35, 394–404 (2018).
pubmed: 30166273
pmcid: 6156706
doi: 10.1016/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).
pubmed: 36746160
doi: 10.1016/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).
pubmed: 8165821
doi: 10.3109/00498259409043220
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).
pubmed: 499320
doi: 10.1007/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).
pubmed: 26993065
doi: 10.2337/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).
pubmed: 30375241
Graham, G. G. et al. Clinical pharmacokinetics of metformin. Clin. Pharmacokinet. 50, 81–98 (2011).
pubmed: 21241070
doi: 10.2165/11534750-000000000-00000
Chandel, N. S. et al. Are metformin doses used in murine cancer models clinically relevant? Cell Metab. 23, 569–570 (2016).
pubmed: 27076070
doi: 10.1016/j.cmet.2016.03.010
He, L. & Wondisford, F. E. Metformin action: concentrations matter. Cell Metab. 21, 159–162 (2015).
pubmed: 25651170
doi: 10.1016/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).
pubmed: 31439934
doi: 10.1038/s41574-019-0242-2
Dowling, R. J. et al. Metformin pharmacokinetics in mouse tumors: implications for human therapy. Cell Metab. 23, 567–568 (2016).
pubmed: 27076069
doi: 10.1016/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).
doi: 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).
pubmed: 32480406
doi: 10.1210/clinem/dgaa332
Singhal, A. et al. Metformin as adjunct antituberculosis therapy. Sci. Transl. Med. 6, 263ra159 (2014).
pubmed: 25411472
doi: 10.1126/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).
pubmed: 23419783
doi: 10.1016/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).
pubmed: 30976851
doi: 10.1007/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).
pubmed: 31758212
doi: 10.1007/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).
pubmed: 25849133
pmcid: 6104807
doi: 10.1038/nm.3787
Zhang, E. et al. Intestinal AMPK modulation of microbiota mediates crosstalk with brown fat to control thermogenesis. Nat. Commun. 13, 1135 (2022).
pubmed: 35241650
pmcid: 8894485
doi: 10.1038/s41467-022-28743-5
Ma, T. et al. Low-dose metformin targets the lysosomal AMPK pathway through PEN2. Nature 603, 159–165 (2022).
pubmed: 35197629
pmcid: 8891018
doi: 10.1038/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).
pubmed: 36656866
pmcid: 9942892
doi: 10.1073/pnas.2211933120
Gormsen, L. C. et al. In vivo imaging of human
pubmed: 27469359
doi: 10.2967/jnumed.116.177774
Bailey, C. J., Wilcock, C. & Scarpello, J. H. Metformin and the intestine. Diabetologia 51, 1552–1553 (2008).
pubmed: 18528677
doi: 10.1007/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).
pubmed: 26869413
doi: 10.1016/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).
pubmed: 35090865
doi: 10.1016/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).
pubmed: 1672896
doi: 10.1111/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).
pubmed: 10718348
doi: 10.1016/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).
pubmed: 27761984
doi: 10.1111/dom.12812
Bailey, C. J. Metformin and intestinal glucose handling. Diabetes Metab. Rev. 11, S23–S32 (1995).
pubmed: 8529481
doi: 10.1002/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).
pubmed: 36942050
pmcid: 10024157
doi: 10.1016/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).
pubmed: 30370686
doi: 10.1111/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).
pubmed: 28778047
doi: 10.1016/j.diabres.2017.07.015
Chang, H. S., Kim, S. J. & Kim, Y. H. Association between colonic
pubmed: 32831962
pmcid: 7429645
doi: 10.1007/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
pubmed: 33236523
doi: 10.1111/dom.14262
Morita, Y. et al. Enhanced release of glucose into the intraluminal space of the intestine associated with metformin treatment as revealed by [
pubmed: 32493754
doi: 10.2337/dc20-0093
Horakova, O. et al. Metformin acutely lowers blood glucose levels by inhibition of intestinal glucose transport. Sci. Rep. 9, 6156 (2019).
pubmed: 30992489
pmcid: 6468119
doi: 10.1038/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).
pubmed: 21852673
pmcid: 3178286
doi: 10.2337/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).
pubmed: 30413829
doi: 10.1007/s00125-018-4759-z
McCreight, L. J., Bailey, C. J. & Pearson, E. R. Metformin and the gastrointestinal tract. Diabetologia 59, 426–435 (2016).
pubmed: 26780750
pmcid: 4742508
doi: 10.1007/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).
pubmed: 34331316
doi: 10.1002/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).
pubmed: 28702329
pmcid: 5485244
doi: 10.1016/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).
pubmed: 25056438
pmcid: 4238005
doi: 10.2337/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).
pubmed: 32672883
pmcid: 7507062
doi: 10.15252/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).
pubmed: 29752759
doi: 10.1111/dom.13362
Bridges, H. R. et al. Structural basis of mammalian respiratory complex I inhibition by medicinal biguanides. Science 379, 351–357 (2023).
pubmed: 36701435
pmcid: 7614227
doi: 10.1126/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).
pubmed: 25017630
doi: 10.1042/BJ20140620
Madiraju, A. K. et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510, 542–546 (2014).
pubmed: 24847880
pmcid: 4074244
doi: 10.1038/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).
pubmed: 35238637
pmcid: 8916010
doi: 10.1073/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).
pubmed: 33849997
doi: 10.2337/db20-1143
Fontaine, E. Metformin-induced mitochondrial complex I inhibition: facts, uncertainties, and consequences. Front. Endocrinol. 9, 753 (2018).
doi: 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).
pubmed: 31343786
doi: 10.1002/biof.1548
Vial, G., Detaille, D. & Guigas, B. Role of mitochondria in the mechanism(s) of action of metformin. Front. Endocrinol. 10, 294 (2019).
doi: 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).
pubmed: 11602624
pmcid: 209533
doi: 10.1172/JCI13505
Shaw, R. J. et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310, 1642–1646 (2005).
pubmed: 16308421
pmcid: 3074427
doi: 10.1126/science.1120781
Zhang, C. S. et al. Metformin activates AMPK through the lysosomal pathway. Cell Metab. 24, 521–522 (2016).
pubmed: 27732831
doi: 10.1016/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).
pubmed: 28089566
pmcid: 5299044
doi: 10.1016/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).
pubmed: 30150719
pmcid: 6207338
doi: 10.1038/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).
pubmed: 23292513
pmcid: 3573218
doi: 10.1038/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).
pubmed: 20577053
pmcid: 2898585
doi: 10.1172/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).
pubmed: 33548500
pmcid: 7921883
doi: 10.1016/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).
pubmed: 24185692
pmcid: 4965268
doi: 10.1038/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).
pubmed: 31801093
pmcid: 6980792
doi: 10.1016/j.celrep.2019.10.117
LaMoia, T. E. & Shulman, G. I. Cellular and molecular mechanisms of metformin action. Endocr. Rev. 42, 77–96 (2021).
pubmed: 32897388
doi: 10.1210/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).
pubmed: 35934089
pmcid: 9623604
doi: 10.1016/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).
pubmed: 10839993
pmcid: 1221104
doi: 10.1042/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).
pubmed: 30591586
doi: 10.1074/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).
pubmed: 24928508
pmcid: 4110255
doi: 10.1074/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).
pubmed: 25002183
doi: 10.1016/j.cmet.2014.06.014
Blazina, I. & Selph, S. Diabetes drugs for nonalcoholic fatty liver disease: a systematic review. Syst. Rev. 8, 295 (2019).
pubmed: 31783920
pmcid: 6884753
doi: 10.1186/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).
pubmed: 24648894
doi: 10.3892/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).
pubmed: 24941111
doi: 10.1021/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).
pubmed: 24403081
pmcid: 3937663
doi: 10.1074/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).
pubmed: 28467931
doi: 10.1016/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).
pubmed: 30038219
pmcid: 6129196
doi: 10.1038/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).
pubmed: 25100057
pmcid: 4154964
doi: 10.1016/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).
pubmed: 17591776
doi: 10.1074/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).
pubmed: 29520235
pmcid: 5827415
doi: 10.3389/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).
pubmed: 30837871
pmcid: 6389785
doi: 10.3389/fphar.2019.00090
Logie, L. et al. Cellular responses to the metal-binding properties of metformin. Diabetes 61, 1423–1433 (2012).
pubmed: 22492524
pmcid: 3357267
doi: 10.2337/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).
pubmed: 10617608
doi: 10.1074/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).
pubmed: 20519126
pmcid: 2935965
doi: 10.1016/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).
pubmed: 35344434
pmcid: 9169108
doi: 10.1073/pnas.2122217119
Karlsson, F. H. et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 498, 99–103 (2013).
pubmed: 23719380
doi: 10.1038/nature12198
Napolitano, A. et al. Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PLoS ONE 9, e100778 (2014).
pubmed: 24988476
pmcid: 4079657
doi: 10.1371/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).
pubmed: 26633628
pmcid: 4681099
doi: 10.1038/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).
pubmed: 27999002
doi: 10.2337/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).
pubmed: 28530702
doi: 10.1038/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).
pubmed: 31953381
pmcid: 6969170
doi: 10.1038/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).
pubmed: 34006565
pmcid: 8323185
doi: 10.2337/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).
pubmed: 33364804
pmcid: 7751595
doi: 10.2147/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).
pubmed: 33658058
pmcid: 7931542
doi: 10.1186/s13073-021-00856-4
Elbere, I. et al. Association of metformin administration with gut microbiome dysbiosis in healthy volunteers. PLoS ONE 13, e0204317 (2018).
pubmed: 30261008
pmcid: 6160085
doi: 10.1371/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).
pubmed: 30904939
pmcid: 6509092
doi: 10.1007/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).
pubmed: 32634783
pmcid: 7377876
doi: 10.18632/aging.103399
Lee, H. & Ko, G. Effect of metformin on metabolic improvement and gut microbiota. Appl. Env. Microbiol. 80, 5935–5943 (2014).
doi: 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).
pubmed: 23804561
doi: 10.1136/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).
pubmed: 29056513
doi: 10.1016/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).
pubmed: 26396057
pmcid: 4585776
doi: 10.1038/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).
doi: 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).
pubmed: 35452877
pmcid: 9096669
doi: 10.1016/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).
pubmed: 31573841
pmcid: 6962505
doi: 10.1152/ajpendo.00245.2019
Adeshirlarijaney, A. & Gewirtz, A. T. Considering gut microbiota in treatment of type 2 diabetes mellitus. Gut Microbes 11, 253–264 (2020).
pubmed: 32005089
pmcid: 7524291
doi: 10.1080/19490976.2020.1717719
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).
pubmed: 34404817
pmcid: 8371110
doi: 10.1038/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).
pubmed: 30397356
pmcid: 6479226
doi: 10.1038/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).
pubmed: 27216492
pmcid: 4930485
doi: 10.1007/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).
pubmed: 34658866
pmcid: 8514724
doi: 10.3389/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).
pubmed: 27180982
pmcid: 4973377
doi: 10.1038/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).
pubmed: 32129462
pmcid: 7302182
doi: 10.1093/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).
pubmed: 31040374
pmcid: 6491483
doi: 10.1038/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).
pubmed: 31515476
pmcid: 6742639
doi: 10.1038/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).
pubmed: 32320607
doi: 10.1021/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).
pubmed: 29988585
pmcid: 6026676
doi: 10.3389/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).
pubmed: 23540700
pmcid: 3898468
doi: 10.1016/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).
pubmed: 31474368
pmcid: 6736778
doi: 10.1016/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).
pubmed: 34329692
doi: 10.1016/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).
pubmed: 33676995
doi: 10.1016/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).
pubmed: 24412651
doi: 10.1016/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).
pubmed: 33782700
pmcid: 8168943
doi: 10.1210/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).
pubmed: 31468642
doi: 10.1111/dom.13869
Zhernakova, A. et al. Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science 352, 565–569 (2016).
pubmed: 27126040
pmcid: 5240844
doi: 10.1126/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).
pubmed: 34389700
pmcid: 8363624
doi: 10.1038/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).
pubmed: 32884086
pmcid: 7471276
doi: 10.1038/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).
doi: 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).
pubmed: 35222739
pmcid: 8872653
doi: 10.1155/2022/6711160
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).
pubmed: 33039709
pmcid: 7553239
doi: 10.1016/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).
pubmed: 36099786
doi: 10.1016/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).
pubmed: 34122067
pmcid: 8191634
doi: 10.3389/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).
pubmed: 36112705
doi: 10.15403/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).
pubmed: 32783890
pmcid: 7546034
doi: 10.1016/j.cmet.2020.07.012
Bonnet, F. & Scheen, A. Understanding and overcoming metformin gastrointestinal intolerance. Diabetes Obes. Metab. 19, 473–481 (2017).
pubmed: 27987248
doi: 10.1111/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).
pubmed: 34844104
doi: 10.1016/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).
pubmed: 32932871
pmcid: 7555986
doi: 10.3390/life10090195
Hotamisligil, G. S. Inflammation, metaflammation and immunometabolic disorders. Nature 542, 177–185 (2017).
pubmed: 28179656
doi: 10.1038/nature21363
Lee, Y. S., Wollam, J. & Olefsky, J. M. An integrated view of immunometabolism. Cell 172, 22–40 (2018).
pubmed: 29328913
pmcid: 8451723
doi: 10.1016/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).
pubmed: 35021057
pmcid: 8773457
doi: 10.1016/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).
pubmed: 35961913
doi: 10.1016/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).
pubmed: 34389841
doi: 10.1038/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).
pubmed: 32533832
doi: 10.1093/cid/ciaa751
Caputa, G., Castoldi, A. & Pearce, E. J. Metabolic adaptations of tissue-resident immune cells. Nat. Immunol. 20, 793–801 (2019).
pubmed: 31213715
doi: 10.1038/s41590-019-0407-0
Kristófi, R. & Eriksson, J. W. Metformin as an anti-inflammatory agent: a short review. J. Endocrinol. 251, R11–R22 (2021).
pubmed: 34463292
doi: 10.1530/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).
pubmed: 31225649
doi: 10.1111/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).
pubmed: 35605453
pmcid: 9124713
doi: 10.1016/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).
pubmed: 29546579
doi: 10.1007/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).
pubmed: 26245802
doi: 10.1002/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).
pubmed: 34876704
doi: 10.1038/s41423-021-00791-9
Xiong, W. et al. Metformin alleviates inflammation through suppressing FASN-dependent palmitoylation of Akt. Cell Death Dis. 12, 934 (2021).
pubmed: 34642298
pmcid: 8511025
doi: 10.1038/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).
pubmed: 34115964
pmcid: 8189765
doi: 10.1016/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).
pubmed: 30318339
doi: 10.1016/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).
pubmed: 30046148
doi: 10.1038/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).
pubmed: 31608061
pmcid: 6773825
doi: 10.3389/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).
pubmed: 32333835
pmcid: 7347426
doi: 10.1016/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).
pubmed: 35822013
pmcid: 9261392
doi: 10.3389/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).
pubmed: 23354371
doi: 10.1097/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).
pubmed: 36054356
doi: 10.1126/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).
pubmed: 32402267
pmcid: 7217133
doi: 10.1016/j.cmet.2020.04.015
Ursini, F. et al. Metformin and autoimmunity: a “new deal” of an old drug. Front. Immunol. 9, 1236 (2018).
pubmed: 29915588
pmcid: 5994909
doi: 10.3389/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
pubmed: 31160534
doi: 10.4049/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).
pubmed: 31105845
pmcid: 6511786
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).
doi: 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).
pubmed: 29271563
doi: 10.1002/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).
pubmed: 32731915
pmcid: 7607149
doi: 10.5483/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).
pubmed: 25003362
doi: 10.1055/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).
pubmed: 30753544
pmcid: 6548897
doi: 10.1093/infdis/jiz064
Böhme, J. et al. Metformin enhances anti-mycobacterial responses by educating CD8
pubmed: 33067434
pmcid: 7567856
doi: 10.1038/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).
pubmed: 32646922
doi: 10.1158/1078-0432.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).
pubmed: 36328378
pmcid: 9639146
doi: 10.1136/jitc-2022-005632
Wabitsch, S. et al. Metformin treatment rescues CD8
pubmed: 35378172
doi: 10.1016/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).
pubmed: 33469052
pmcid: 7815730
doi: 10.1038/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).
pubmed: 15849206
pmcid: 558205
doi: 10.1136/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).
pubmed: 28776080
pmcid: 5709147
doi: 10.1007/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).
pubmed: 34873484
pmcid: 8640802
Badrick, E. & Renehan, A. G. Diabetes and cancer: 5 years into the recent controversy. Eur. J. Cancer 50, 2119–2125 (2014).
pubmed: 24930060
doi: 10.1016/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).
pubmed: 35608580
pmcid: 9131745
doi: 10.1001/jama.2022.6147
Skuli, S. J. et al. Metformin and cancer, an ambiguanidous relationship. Pharmaceuticals 15, 626 (2022).
pubmed: 35631452
pmcid: 9144507
doi: 10.3390/ph15050626
Heng, T. S. & Painter, M. W. The Immunological Genome Project: networks of gene expression in immune cells. Nat. Immunol. 9, 1091–1094 (2008).
pubmed: 18800157
doi: 10.1038/ni1008-1091
Jones, R. C. et al. The Tabula Sapiens: a multiple-organ, single-cell transcriptomic atlas of humans. Science 376, eabl4896 (2022).
pubmed: 35549404
doi: 10.1126/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).
pubmed: 30995468
pmcid: 6484776
doi: 10.1016/j.celrep.2019.03.067
Zhao, H., Swanson, K. D. & Zheng, B. Therapeutic repurposing of biguanides in cancer. Trends Cancer 7, 714–730 (2021).
pubmed: 33865798
pmcid: 8295194
doi: 10.1016/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).
pubmed: 28770328
pmcid: 5709209
doi: 10.1007/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).
pubmed: 21386129
pmcid: 3082009
doi: 10.18632/aging.100273
Espada, L. et al. Loss of metabolic plasticity underlies metformin toxicity in aged Caenorhabditis elegans. Nat. Metab. 2, 1316–1331 (2020).
pubmed: 33139960
doi: 10.1038/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).
doi: 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).
pubmed: 32271993
doi: 10.1002/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).
pubmed: 32444366
pmcid: 7243801
doi: 10.1136/bmj.m1966
Cai, Q. et al. Obesity and COVID-19 severity in a designated hospital in Shenzhen, China. Diabetes Care 43, 1392–1398 (2020).
pubmed: 32409502
doi: 10.2337/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).
pubmed: 32369736
pmcid: 7252168
doi: 10.1016/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).
pubmed: 33479538
doi: 10.1038/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).
pubmed: 32861268
pmcid: 7439986
doi: 10.1016/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).
pubmed: 32353859
pmcid: 7431030
doi: 10.1038/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).
pubmed: 34357881
pmcid: 8492301
doi: 10.1172/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).
pubmed: 34858397
pmcid: 8631967
doi: 10.3389/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).
pubmed: 34927127
Bramante, C. T. et al. Randomized trial of metformin, ivermectin, and fluvoxamine for Covid-19. N. Engl. J. Med. 387, 599–610 (2022).
pubmed: 36070710
pmcid: 9945922
doi: 10.1056/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).
pubmed: 27974345
doi: 10.2337/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).
pubmed: 30178545
doi: 10.1111/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).
pubmed: 36001956
doi: 10.1016/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).
pubmed: 36435271
doi: 10.1016/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).
pubmed: 34849709
doi: 10.1210/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).
pubmed: 28846099
doi: 10.1038/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).
pubmed: 28846097
doi: 10.1038/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).
doi: 10.2337/dc11-1299
Ning, H. H. et al. The effects of metformin on simple obesity: a meta-analysis. Endocrine 62, 528–534 (2018).
pubmed: 30151735
doi: 10.1007/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).
pubmed: 36273168
pmcid: 9588202
doi: 10.1186/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).
pubmed: 36444166
pmcid: 9789395
doi: 10.1111/1753-0407.13334
Kincaid, J. W. R. & Coll, A. P. Metformin and GDF15: where are we now? Nat. Rev. Endocrinol. 19, 6–7 (2022).
doi: 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).
pubmed: 30841429
doi: 10.1016/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).
pubmed: 27641099
pmcid: 5061633
doi: 10.1016/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).
pubmed: 24270984
doi: 10.2337/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).
pubmed: 28158227
pmcid: 5291441
doi: 10.1371/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).
pubmed: 16952199
doi: 10.1002/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).
pubmed: 8354343
doi: 10.1016/0922-4106(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).
pubmed: 34736121
pmcid: 8577482
doi: 10.1016/j.redox.2021.102171
Yang, D. et al. A nationwide wastewater-based assessment of metformin consumption across Australia. Env. Int. 165, 107282 (2022).
doi: 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).
doi: 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).
pubmed: 31726346
doi: 10.1016/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).
pubmed: 35697083
doi: 10.1016/j.envres.2022.113613
Ambrosio-Albuquerque, E. P. et al. Metformin environmental exposure: a systematic review. Environ. Toxicol. Pharmacol. 83, 103588 (2021).
pubmed: 33460803
doi: 10.1016/j.etap.2021.103588
Wilkinson, J. L. et al. Pharmaceutical pollution of the world’s rivers. Proc. Natl Acad. Sci. USA 119, e2113947119 (2022).
pubmed: 35165193
pmcid: 8872717
doi: 10.1073/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).
pubmed: 29248761
doi: 10.1016/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).
pubmed: 35843324
doi: 10.1016/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).
pubmed: 34311114
pmcid: 8446320
doi: 10.1016/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).
doi: 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).
doi: 10.1021/acs.est.2c07669