Metformin in Diabetes Management and Immune Modulation: A Comprehensive Review
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Abstract
Metformin is a primary treatment for type 2 diabetes (T2D), well-known for its ability to lower blood glucose levels through both AMP-activated protein kinase (AMPK)-dependent and -independent pathways. Recent evidence suggests that metformin also possesses immunomodulatory properties, indicating its potential as a therapeutic agent that extends beyond metabolic regulation. This review summarizes the current understanding of metformin's dual roles in managing diabetes and modulating the immune system. It also explores the underlying mechanisms, clinical implications, and potential directions for future research.
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3. Geerlings SE HA. Immune dysfunction in patients with diabetes mellitus (DM). FEMS Immunol Med Microbiol. 1999;26(3-4):259-265.
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5. Lenzi A CMCFBIPAMFCCBLCVMSBM. Quantitative changes in serum IL-8, TNF-α and TGF-β1 levels depending on compensation stage in type 2 diabetic patients. Int J Diabetes Metab. 2009;17(2):59-62.
6. Bonaventura P, Benedetti G, Albarède F, Miossec P. Zinc and its role in immunity and inflammation. Autoimmun Rev. 2015;14(4):277-285. doi:10.1016/j.autrev.2014.11.008
7. Lecube A, Pachón G, Petriz J, Hernández C, Simó R. Phagocytic activity is impaired in type 2 diabetes mellitus and increases after metabolic improvement. PLoS One. 2011;6(8):e23366. doi:10.1371/journal.pone.0023366
8. Zhou T, Xu X, Du M, Zhao T, Wang J. A preclinical overview of metformin for the treatment of type 2 diabetes. Biomed Pharmacother. 2018;106:1227-1235. doi:10.1016/j.biopha.2018.07.085
9. Mueller NT, Differding MK, Zhang M, et al. Metformin Affects Gut Microbiome Composition and Function and Circulating Short- Chain Fatty Acids: A Randomized Trial. Diabetes Care. 2021;44(7):1462-1471.
10. Soukas AA, Hao H WL. Metformin as anti-aging therapy: is it for everyone? Trends Endocrinol Metab. 2019;30(10):745-55.
11. Kheirandish M, Mahboobi H, Yazdanparast M, Kamal W KM. Anti-Cancer Effects of Metformin: Recent Evidences for its Role in Prevention and Treatment of Cancer. Curr Drug Metab. 2018;19(9):793-7.
12. Driver C, Bamitale KD, Kazi A, Olla M, Nyane NA OP. Cardioprotective effects of metformin. J Cardiovasc Pharmacol. 2018;72(2):121-127. doi:10.1097/FJC.0000000000000599
13. Mohammadi Y RFA. Effect of metformin on the expression of SNARE proteins in the skeletal muscle of rats with type 2 diabetes. J Sci Res Med Sci. 2021;28(3):270-278.
14. Song S, Andrikopoulos S, Filippis C, Thorburn AW, Khan D, Proietto J. Mechanism of fat-induced hepatic gluconeogenesis: effect of metformin. Am J Physiol Metab. 2001;281(2):E275-82.
15. Kim YD, Park KG, Lee YS, et al. Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase–dependent regulation of the orphan nuclear receptor SHP. Diabetes. 2008;57(2):306-314.
16. Salani B, Del Rio A, Marini C, Sambuceti G, Cordera R, D. M. Metformin, cancer and glucose metabolism. Endocr Relat Cancer. 2014;21(6):R461-71.
17. Wang C, Liu F, Yuan Y, et al. Metformin Suppresses Lipid Accumulation in Skeletal Muscle by Promoting Fatty Acid Oxidation. Clin Lab. 2014;60(6):887-96.
18. Aatsinki SM, Buler M, Salomäki H, Koulu M, Pavek P, Hakkola J. Metformin induces PGC-1α expression and selectively affects hepatic PGC-1α functions. Br J Pharmacol. 2014;171(9):2351-2363. doi:10.1111/bph.12585
19. Iorio R, Celenza G PS. Mitophagy: Molecular Mechanisms, New Concepts on Parkin Activation and the Emerging Role of AMPK/ULK1 Axis. Cells. 2021;11(1):30-55.
20. Xiang M, Yuan X, Zhang N, et al. Effects of exercise, metformin, and combination treatments on type 2 diabetic mellitus-induced muscle atrophy in db/db mice: Crosstalk between autophagy and the proteasome. J Physiol Biochem. 2024;80(1):235-247.
21. Longo S, Rizza S, Federici M. Microbiota-gut-brain axis: relationships among the vagus nerve, gut microbiota, obesity, and diabetes. Acta Diabetol. 2023;60(8):1007-1017. doi:10.1007/s00592-023-02088-x
22. Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B. Metformin: From Mechanisms of Action to Therapies. Cell Metab. 2014;20(6):953-966.
23. Foretz M, Guigas B, Viollet B. Metformin: update on mechanisms of action and repurposing potential. Nat Rev Endocrinol. 2023;19(8):460-476.
24. Zafar-Mohammadi K, Poursamimi J, Atabaki M. NLRP3 inflammasome activation and its inhibitory drugs in connection with COVID-19 infection. Eur J Inflamm. 2022;20:1721727X221130984.
25. Yang F, Qin Y, Wang Y, et al. Metformin Inhibits the NLRP3 Inflammasome via AMPK/mTOR-dependent Effects in Diabetic Cardiomyopathy. Int J Biol Sci. 2019;15(5):1010-1019.
26. Cameron AR, Morrison VL, Levin D, et al. Anti-inflammatory effects of metformin irrespective of diabetes status. Circ Res. 2016;119(5):652-665.
27. Kalender A, Selvaraj A, Kim SY, Gulati P, Brûlé S, Viollet B, Kemp BE, Bardeesy N, Dennis P, Schlager JJ MA. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab. 2010;11(5):390-401.
28. Duan W, Ding Y, Yu X, et al. Metformin mitigates autoimmune insulitis by inhibiting Th1 and Th17 responses while promoting Treg production. Am J Transl Res. 2019;11(4):2393-2402. http://www.ncbi.nlm.nih.gov/pubmed/31105845%0Ahttp://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC6511786
29. Zhao M, Li XW, Chen DZ, et al. Neuro-Protective role of metformin in patients with acute stroke and type 2 diabetes mellitus via ampk/mammalian target of rapamycin (mTOR) signaling pathway and oxidative stress. Med Sci Monit. 2019;25:2186-2194. doi:10.12659/MSM.911250
30. Xiao N, Wang J, Wang T, Xiong X, Zhou J, Su X. Metformin abrogates pathological TNF-α-producing B cells through mTOR-dependent metabolic reprogramming in polycystic ovary syndrome. Elife. 2022;11(e74713):1-19. doi:10.7554/eLife.74713
31. Lee SY, Moon SJ, Kim EK, et al. Metformin suppresses systemic autoimmunity in Roquinsan/san mice through inhibiting B cell differentiation into plasma cells via regulation of AMPK/mTOR/STAT3. J Immunol. 2017;198(7):2661-70.
32. Chen X, Ma J, Yao Y, et al. Metformin prevents BAFF activation of Erk1/2 from B-cell proliferation and survival by impeding mTOR-PTEN/Akt signaling pathway. Int Immunopharmacol. 2021;96(107771):1-10.
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| Diabetes Mellitus Type 2; Metformin; Innate Immunity; NLRP3 protein; Clinical trials | ||
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Ghafari M, Poursamimi J, Asli F. Metformin in Diabetes Management and Immune Modulation: A Comprehensive Review. Iran J Allergy Asthma Immunol. 2025;:1-15.
