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Current Drug Targets

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ISSN (Print): 1389-4501
ISSN (Online): 1873-5592

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Review Article

Metformin: A Promising Antidiabetic Medication for Cancer Treatment

Author(s): Wei Mu*, Yunyun Jiang, Guoqiang Liang, Yue Feng and Falin Qu

Volume 24, Issue 1, 2023

Published on: 23 November, 2022

Page: [41 - 54] Pages: 14

DOI: 10.2174/1389450124666221104094918

Price: $65

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Abstract

Metformin is a widely used drug in patients with type 2 diabetes mellitus. Metformin inhibits hepatic gluconeogenesis and increases glucose utilization in peripheral tissues. In recent years, several studies have shown that metformin is a potential therapeutic agent against cancer, alone or combined with other anticancer treatments. Metformin mainly activates the AMPK complex and regulates intracellular energy status, inhibiting the mitochondrial respiratory chain complex I and reducing the production of reactive oxygen species. Other anticancer targets of metformin are specific transcription factors inhibiting cell proliferation, promoting apoptosis and reducing drug resistance. In addition, metformin modulates tumor cells' response to anticancer treatments, favoring the activity of T cells. In diabetic patients, metformin reduces the occurrence of cancer and improves the prognosis and efficacy of anticancer treatments. In this review, we provided a comprehensive perspective of metformin as an anticancer drug.

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[1]
Schwarz PEH, Gallein G, Ebermann D, et al. Global diabetes survey-an annual report on quality of diabetes care. Diabetes Res Clin Pract 2013; 100(1): 11-8.
[http://dx.doi.org/10.1016/j.diabres.2012.11.008] [PMID: 23333041]
[2]
Bailey CJ, Turner RC. Metformin. N Engl J Med 1996; 334(9): 574-9.
[http://dx.doi.org/10.1056/NEJM199602293340906] [PMID: 8569826]
[3]
Scarpello JHB, Howlett HCS. Metformin therapy and clinical uses. Diab Vasc Dis Res 2008; 5(3): 157-67.
[http://dx.doi.org/10.3132/dvdr.2008.027] [PMID: 18777488]
[4]
Bahne E, Sun EWL, Young RL, et al. Metformin-induced glucagon-like peptide-1 secretion contributes to the actions of metformin in type 2 diabetes. JCI Insight 2018; 3(23): e93936.
[http://dx.doi.org/10.1172/jci.insight.93936] [PMID: 30518693]
[5]
Hunter RW, Hughey CC, Lantier L, et al. Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase. Nat Med 2018; 24(9): 1395-406.
[http://dx.doi.org/10.1038/s41591-018-0159-7] [PMID: 30150719]
[6]
Forslund K, Hildebrand F, Nielsen T, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 2015; 528(7581): 262-6.
[http://dx.doi.org/10.1038/nature15766] [PMID: 26633628]
[7]
Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JMM. New users of metformin are at low risk of incident cancer: A cohort study among people with type 2 diabetes. Diabetes Care 2009; 32(9): 1620-5.
[http://dx.doi.org/10.2337/dc08-2175] [PMID: 19564453]
[8]
Pernicova I, Korbonits M. Metformin—mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol 2014; 10(3): 143-56.
[http://dx.doi.org/10.1038/nrendo.2013.256] [PMID: 24393785]
[9]
Zhou Z, Tang Y, Jin X, et al. Metformin inhibits advanced glycation end products-induced inflammatory response in murine macrophages partly through ampk activation and rage/nfkappab pathway suppression. J Diabetes Res 2016; 2016: 1-10.
[http://dx.doi.org/10.1155/2016/4847812] [PMID: 27761470]
[10]
Madiraju AK, Erion DM, Rahimi Y, et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 2014; 510(7506): 542-6.
[http://dx.doi.org/10.1038/nature13270] [PMID: 24847880]
[11]
Zheng D, MacLean PS, Pohnert SC, et al. Regulation of muscle glut-4 transcription by amp-activated protein kinase. J Appl Physiol 2001; 91(3): 1073-83.
[http://dx.doi.org/10.1152/jappl.2001.91.3.1073]
[12]
Nakada D, Saunders TL, Morrison SJ. Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 2010; 468(7324): 653-8.
[http://dx.doi.org/10.1038/nature09571] [PMID: 21124450]
[13]
Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 2013; 494(7436): 256-60.
[http://dx.doi.org/10.1038/nature11808] [PMID: 23292513]
[14]
Shaw RJ, Lamia KA, Vasquez D, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 2005; 310(5754): 1642-6.
[http://dx.doi.org/10.1126/science.1120781] [PMID: 16308421]
[15]
Foretz M, Hébrard S, Leclerc J, et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest 2010; 120(7): 2355-69.
[http://dx.doi.org/10.1172/JCI40671] [PMID: 20577053]
[16]
Howell JJ, Hellberg K, Turner M, et al. Metformin inhibits hepatic mtorc1 signaling via dose-dependent mechanisms involving ampk and the tsc complex. Cell Metab 2017; 25(2): 463-71.
[http://dx.doi.org/10.1016/j.cmet.2016.12.009] [PMID: 28089566]
[17]
He L, Sabet A, Djedjos S, et al. Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell 2009; 137(4): 635-46.
[http://dx.doi.org/10.1016/j.cell.2009.03.016] [PMID: 19450513]
[18]
Schäfer G. Site-specific uncoupling and inhibition of oxidative phosphorylation by biguanides. II. Biochim Biophys Acta Bioenerg 1969; 172(2): 334-7.
[http://dx.doi.org/10.1016/0005-2728(69)90077-2] [PMID: 4304727]
[19]
El-Mir MY, Nogueira V, Fontaine E, Avéret N, Rigoulet M, Leverve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 2000; 275(1): 223-8.
[http://dx.doi.org/10.1074/jbc.275.1.223] [PMID: 10617608]
[20]
Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 2000; 348(3): 607-14.
[http://dx.doi.org/10.1042/bj3480607] [PMID: 10839993]
[21]
Wilcock C, Wyre ND, Bailey CJ. Subcellular distribution of metformin in rat liver. J Pharm Pharmacol 2011; 43(6): 442-4.
[http://dx.doi.org/10.1111/j.2042-7158.1991.tb03507.x] [PMID: 1681061]
[22]
Bridges HR, Jones AJY, Pollak MN, Hirst J. Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem J 2014; 462(3): 475-87.
[http://dx.doi.org/10.1042/BJ20140620] [PMID: 25017630]
[23]
Batandier C, Guigas B, Detaille D, et al. The ROS production induced by a reverse-electron flux at respiratory-chain complex 1 is hampered by metformin. J Bioenerg Biomembr 2006; 38(1): 33-42.
[http://dx.doi.org/10.1007/s10863-006-9003-8] [PMID: 16732470]
[24]
Cameron AR, Logie L, Patel K, et al. Metformin selectively targets redox control of complex I energy transduction. Redox Biol 2018; 14: 187-97.
[http://dx.doi.org/10.1016/j.redox.2017.08.018] [PMID: 28942196]
[25]
Fontaine E. Metformin-induced mitochondrial complex i inhibition: Facts, uncertainties, and consequences. Front Endocrinol 2018; 9: 753.
[http://dx.doi.org/10.3389/fendo.2018.00753] [PMID: 30619086]
[26]
Heckman-Stoddard BM, DeCensi A, Sahasrabuddhe VV, Ford LG. Repurposing metformin for the prevention of cancer and cancer recurrence. Diabetologia 2017; 60(9): 1639-47.
[http://dx.doi.org/10.1007/s00125-017-4372-6] [PMID: 28776080]
[27]
Kurelac I, Iommarini L, Vatrinet R, et al. Inducing cancer indolence by targeting mitochondrial Complex I is potentiated by blocking macrophage-mediated adaptive responses. Nat Commun 2019; 10(1): 903.
[http://dx.doi.org/10.1038/s41467-019-08839-1] [PMID: 30796225]
[28]
Vial G, Detaille D, Guigas B. Role of mitochondria in the mechanism(s) of action of metformin. Front Endocrinol 2019; 10: 294.
[http://dx.doi.org/10.3389/fendo.2019.00294] [PMID: 31133988]
[29]
Fullerton MD, Galic S, Marcinko K, et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat Med 2013; 19(12): 1649-54.
[http://dx.doi.org/10.1038/nm.3372] [PMID: 24185692]
[30]
Logie L, Harthill J, Patel K, et al. Cellular responses to the metal-binding properties of metformin. Diabetes 2012; 61(6): 1423-33.
[http://dx.doi.org/10.2337/db11-0961] [PMID: 22492524]
[31]
Degli Esposti M. Inhibitors of NADH–ubiquinone reductase: An overview. Biochim Biophys Acta Bioenerg 1998; 1364(2): 222-35.
[http://dx.doi.org/10.1016/S0005-2728(98)00029-2] [PMID: 9593904]
[32]
Hardie DG. AMPK-sensing energy while talking to other signaling pathways. Cell Metab 2014; 20(6): 939-52.
[http://dx.doi.org/10.1016/j.cmet.2014.09.013] [PMID: 25448702]
[33]
Dujic T, Zhou K, Yee SW, et al. Variants in pharmacokinetic transporters and glycemic response to metformin: A metgen meta-analysis. Clin Pharmacol Ther 2017; 101(6): 763-72.
[http://dx.doi.org/10.1002/cpt.567] [PMID: 27859023]
[34]
DeFronzo RA, Buse JB, Kim T, 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 2016; 59(8): 1645-54.
[http://dx.doi.org/10.1007/s00125-016-3992-6] [PMID: 27216492]
[35]
Brønden A, Albér A, Rohde U, et al. Single-dose metformin enhances bile acid-induced glucagon-like peptide-1 secretion in patients with type 2 diabetes. J Clin Endocrinol Metab 2017; 102(11): 4153-62.
[http://dx.doi.org/10.1210/jc.2017-01091] [PMID: 28938439]
[36]
DeCensi A, Puntoni M, Goodwin P, et al. Metformin and cancer risk in diabetic patients: A systematic review and meta-analysis. Cancer Prev Res 2010; 3(11): 1451-61.
[http://dx.doi.org/10.1158/1940-6207.CAPR-10-0157] [PMID: 20947488]
[37]
Zi F, Zi H, Li Y, He J, Shi Q, Cai Z. Metformin and cancer: An existing drug for cancer prevention and therapy. (Review). Oncol Lett 2017; 15(1): 683-90.
[http://dx.doi.org/10.3892/ol.2017.7412] [PMID: 29422962]
[38]
Saxton RA, Sabatini DM. Mtor signaling in growth, metabolism, and disease. Cell 2017; 168(6): 960-76.
[http://dx.doi.org/10.1016/j.cell.2017.02.004] [PMID: 28283069]
[39]
Warburg O. On the origin of cancer cells. Science 1956; 123(3191): 309-14.
[http://dx.doi.org/10.1126/science.123.3191.309] [PMID: 13298683]
[40]
Ward PS, Thompson CB. Metabolic reprogramming: A cancer hallmark even warburg did not anticipate. Cancer Cell 2012; 21(3): 297-308.
[http://dx.doi.org/10.1016/j.ccr.2012.02.014] [PMID: 22439925]
[41]
Wu D, Hu D, Chen H, et al. Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer. Nature 2018; 559(7715): 637-41.
[http://dx.doi.org/10.1038/s41586-018-0350-5] [PMID: 30022161]
[42]
Ko M, Huang Y, Jankowska AM, et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 2010; 468(7325): 839-43.
[http://dx.doi.org/10.1038/nature09586] [PMID: 21057493]
[43]
Wang Y, Zhang Y. Regulation of TET protein stability by calpains. Cell Rep 2014; 6(2): 278-84.
[http://dx.doi.org/10.1016/j.celrep.2013.12.031] [PMID: 24412366]
[44]
Williams K, Christensen J, Pedersen MT, et al. TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 2011; 473(7347): 343-8.
[http://dx.doi.org/10.1038/nature10066] [PMID: 21490601]
[45]
Xu Y, Wu F, Tan L, et al. Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells. Mol Cell 2011; 42(4): 451-64.
[http://dx.doi.org/10.1016/j.molcel.2011.04.005] [PMID: 21514197]
[46]
Fruehauf JP, Meyskens FL Jr. Reactive oxygen species: A breath of life or death? Clin Cancer Res 2007; 13(3): 789-94.
[http://dx.doi.org/10.1158/1078-0432.CCR-06-2082] [PMID: 17289868]
[47]
Poillet-Perez L, Despouy G, Delage-Mourroux R, Boyer-Guittaut M. Interplay between ROS and autophagy in cancer cells, from tumor initiation to cancer therapy. Redox Biol 2015; 4: 184-92.
[http://dx.doi.org/10.1016/j.redox.2014.12.003] [PMID: 25590798]
[48]
Toyokuni S. Molecular mechanisms of oxidative stress-induced carcinogenesis: From epidemiology to oxygenomics. IUBMB Life 2008; 60(7): 441-7.
[http://dx.doi.org/10.1002/iub.61] [PMID: 18465793]
[49]
Storz P. Reactive oxygen species in tumor progression. Front Biosci 2005; 10(1-3): 1881-96.
[http://dx.doi.org/10.2741/1667] [PMID: 15769673]
[50]
Kudin AP, Bimpong-Buta NYB, Vielhaber S, Elger CE, Kunz WS. Characterization of superoxide-producing sites in isolated brain mitochondria. J Biol Chem 2004; 279(6): 4127-35.
[http://dx.doi.org/10.1074/jbc.M310341200] [PMID: 14625276]
[51]
Guigas B, Detaille D, Chauvin C, et al. Metformin inhibits mitochondrial permeability transition and cell death: A pharmacological in vitro study. Biochem J 2004; 382(3): 877-84.
[http://dx.doi.org/10.1042/BJ20040885] [PMID: 15175014]
[52]
Detaille D, Guigas B, Chauvin C, et al. Metformin prevents high-glucose-induced endothelial cell death through a mitochondrial permeability transition-dependent process. Diabetes 2005; 54(7): 2179-87.
[http://dx.doi.org/10.2337/diabetes.54.7.2179] [PMID: 15983220]
[53]
Chauvin C, De Oliveira F, Ronot X, Mousseau M, Leverve X, Fontaine E. Rotenone inhibits the mitochondrial permeability transition-induced cell death in U937 and KB cells. J Biol Chem 2001; 276(44): 41394-8.
[http://dx.doi.org/10.1074/jbc.M106417200] [PMID: 11527970]
[54]
Oh JE, Han JA, Hwang ES. Downregulation of transcription factor, Sp1, during cellular senescence. Biochem Biophys Res Commun 2007; 353(1): 86-91.
[http://dx.doi.org/10.1016/j.bbrc.2006.11.118] [PMID: 17161377]
[55]
Guan H, Cai J, Zhang N, et al. Sp1 is upregulated in human glioma, promotes MMP-2-mediated cell invasion and predicts poor clinical outcome. Int J Cancer 2012; 130(3): 593-601.
[http://dx.doi.org/10.1002/ijc.26049] [PMID: 21469139]
[56]
Safe S, Nair V, Karki K. Metformin-induced anticancer activities: Recent insights. Biol Chem 2018; 399(4): 321-35.
[http://dx.doi.org/10.1515/hsz-2017-0271] [PMID: 29272251]
[57]
Nair V, Pathi S, Jutooru I, et al. Metformin inhibits pancreatic cancer cell and tumor growth and downregulates Sp transcription factors. Carcinogenesis 2013; 34(12): 2870-9.
[http://dx.doi.org/10.1093/carcin/bgt231] [PMID: 23803693]
[58]
Safe S, Abbruzzese J, Abdelrahim M, Hedrick E. Specificity protein transcription factors and cancer: Opportunities for drug development. Cancer Prev Res 2018; 11(7): 371-82.
[http://dx.doi.org/10.1158/1940-6207.CAPR-17-0407] [PMID: 29545399]
[59]
Lou Z, O’Reilly S, Liang H, Maher VM, Sleight SD, McCormick JJ. Down-regulation of overexpressed sp1 protein in human fibrosarcoma cell lines inhibits tumor formation. Cancer Res 2005; 65(3): 1007-17.
[http://dx.doi.org/10.1158/0008-5472.1007.65.3] [PMID: 15705902]
[60]
Sahra IB, Laurent K, Loubat A, et al. The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene 2008; 27(25): 3576-86.
[http://dx.doi.org/10.1038/sj.onc.1211024] [PMID: 18212742]
[61]
Kim HG, Hien TT, Han EH, et al. Metformin inhibits P-glycoprotein expression via the NF-κB pathway and CRE transcriptional activity through AMPK activation. Br J Pharmacol 2011; 162(5): 1096-108.
[http://dx.doi.org/10.1111/j.1476-5381.2010.01101.x] [PMID: 21054339]
[62]
Ardito CM, Grüner BM, Takeuchi KK, et al. EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell 2012; 22(3): 304-17.
[http://dx.doi.org/10.1016/j.ccr.2012.07.024] [PMID: 22975374]
[63]
Navas C, Hernández-Porras I, Schuhmacher AJ, Sibilia M, Guerra C, Barbacid M. EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma. Cancer Cell 2012; 22(3): 318-30.
[http://dx.doi.org/10.1016/j.ccr.2012.08.001] [PMID: 22975375]
[64]
Safe S, Imanirad P, Sreevalsan S, Nair V, Jutooru I. Transcription factor Sp1, also known as specificity protein 1 as a therapeutic target. Expert Opin Ther Targets 2014; 18(7): 759-69.
[http://dx.doi.org/10.1517/14728222.2014.914173] [PMID: 24793594]
[65]
Finlay D, Cantrell DA. Metabolism, migration and memory in cytotoxic T cells. Nat Rev Immunol 2011; 11(2): 109-17.
[http://dx.doi.org/10.1038/nri2888] [PMID: 21233853]
[66]
Blagih J, Coulombe F, Vincent EE, et al. The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity 2015; 42(1): 41-54.
[http://dx.doi.org/10.1016/j.immuni.2014.12.030] [PMID: 25607458]
[67]
Scharping NE, Menk AV, Moreci RS, et al. The tumor microenvironment represses t cell mitochondrial biogenesis to drive intratumoral t cell metabolic insufficiency and dysfunction. Immunity 2016; 45(3): 701-3.
[http://dx.doi.org/10.1016/j.immuni.2016.08.009] [PMID: 27653602]
[68]
Cha JH, Yang WH, Xia W, et al. Metformin promotes antitumor immunity via endoplasmic-reticulum-associated degradation of pd-l1. Mol Cell 2018; 71(4): 606-20.
[http://dx.doi.org/10.1016/j.molcel.2018.07.030] [PMID: 30118680]
[69]
Pearce EL, Walsh MC, Cejas PJ, et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 2009; 460(7251): 103-7.
[http://dx.doi.org/10.1038/nature08097] [PMID: 19494812]
[70]
Eikawa S, Nishida M, Mizukami S, Yamazaki C, Nakayama E, Udono H. Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proc Natl Acad Sci 2015; 112(6): 1809-14.
[http://dx.doi.org/10.1073/pnas.1417636112] [PMID: 25624476]
[71]
de Oliveira S, Houseright RA, Graves AL, et al. Metformin modulates innate immune-mediated inflammation and early progression of NAFLD-associated hepatocellular carcinoma in zebrafish. J Hepatol 2019; 70(4): 710-21.
[http://dx.doi.org/10.1016/j.jhep.2018.11.034] [PMID: 30572006]
[72]
Alsaab HO, Sau S, Alzhrani R, et al. Pd-1 and pd-l1 checkpoint signaling inhibition for cancer immunotherapy: Mechanism, combinations, and clinical outcome. Front Pharmacol 2017; 8: 561.
[http://dx.doi.org/10.3389/fphar.2017.00561] [PMID: 28878676]
[73]
Ding L, Liang G, Yao Z, et al. Metformin prevents cancer metastasis by inhibiting M2-like polarization of tumor associated macrophages. Oncotarget 2015; 6(34): 36441-55.
[http://dx.doi.org/10.18632/oncotarget.5541] [PMID: 26497364]
[74]
Saito A, Kitayama J, Horie H, et al. Metformin changes the immune microenvironment of colorectal cancer in patients with type 2 diabetes mellitus. Cancer Sci 2020; 111(11): 4012-20.
[http://dx.doi.org/10.1111/cas.14615] [PMID: 32794612]
[75]
Abd El-Fattah EE, Zakaria AY. Metformin modulate immune fitness in hepatocellular carcinoma: Molecular and cellular approach. Int Immunopharmacol 2022; 109: 108889.
[http://dx.doi.org/10.1016/j.intimp.2022.108889] [PMID: 35679661]
[76]
Curry JM, Johnson J, Mollaee M, et al. Metformin clinical trial in hpv+ and hpv- head and neck squamous cell carcinoma: Impact on cancer cell apoptosis and immune infiltrate. Front Oncol 2018; 8: 436.
[http://dx.doi.org/10.3389/fonc.2018.00436] [PMID: 30364350]
[77]
Hartwig J, Loebel M, Steiner S, et al. Metformin attenuates ros via foxo3 activation in immune cells. Front Immunol 2021; 12: 581799.
[http://dx.doi.org/10.3389/fimmu.2021.581799] [PMID: 33953705]
[78]
Wabitsch S, McCallen JD, Kamenyeva O, et al. Metformin treatment rescues CD8+ T-cell response to immune checkpoint inhibitor therapy in mice with NAFLD. J Hepatol 2022; 77(3): 748-60.
[http://dx.doi.org/10.1016/j.jhep.2022.03.010] [PMID: 35378172]
[79]
Pereira FV, Melo ACL, Low JS, et al. Metformin exerts antitumor activity via induction of multiple death pathways in tumor cells and activation of a protective immune response. Oncotarget 2018; 9(40): 25808-25.
[http://dx.doi.org/10.18632/oncotarget.25380] [PMID: 29899823]
[80]
Lee SK, Park MJ, Jhun JY, et al. Combination treatment with metformin and tacrolimus improves systemic immune cellular homeostasis by modulating treg and th17 imbalance. Front Immunol 2021; 11: 581728.
[http://dx.doi.org/10.3389/fimmu.2020.581728] [PMID: 33488583]
[81]
Falah RR, Talib WH, Shbailat SJ. Combination of metformin and curcumin targets breast cancer in mice by angiogenesis inhibition, immune system modulation and induction of p53 independent apoptosis. Ther Adv Med Oncol 2017; 9(4): 235-52.
[http://dx.doi.org/10.1177/1758834016687482] [PMID: 28491145]
[82]
Franco F, Jaccard A, Romero P, Yu YR, Ho PC. Metabolic and epigenetic regulation of T-cell exhaustion. Nat Metab 2020; 2(10): 1001-12.
[http://dx.doi.org/10.1038/s42255-020-00280-9] [PMID: 32958939]
[83]
Klement JD, Paschall AV, Redd PS, et al. An osteopontin/CD44 immune checkpoint controls CD8+ T cell activation and tumor immune evasion. J Clin Invest 2018; 128(12): 5549-60.
[http://dx.doi.org/10.1172/JCI123360] [PMID: 30395540]
[84]
Marcucci F, Romeo E, Caserta CA, Rumio C, Lefoulon F. Context-dependent pharmacological effects of metformin on the immune system. Trends Pharmacol Sci 2020; 41(3): 162-71.
[http://dx.doi.org/10.1016/j.tips.2020.01.003] [PMID: 32033771]
[85]
Schott S, Bierhaus A, Schuetz F, et al. Therapeutic effects of metformin in breast cancer: Involvement of the immune system? Cancer Immunol Immunother 2011; 60(9): 1221-5.
[http://dx.doi.org/10.1007/s00262-011-1062-y] [PMID: 21681370]
[86]
Watanabe M, Yamamoto H, Eikawa S, et al. Study about the efficacy of metformin to immune function in cancer patients. Acta Med Okayama 2016; 70(4): 327-30.
[http://dx.doi.org/10.18926/AMO/54514] [PMID: 27549683]
[87]
Schuiveling M, Vazirpanah N, Radstake TRDJ, Zimmermann M, Broen JCA. Metformin, a new era for an old drug in the treatment of immune mediated disease? Curr Drug Targets 2018; 19(8): 945-59.
[http://dx.doi.org/10.2174/1389450118666170613081730] [PMID: 28606032]
[88]
Zhang Y, Wang H, Xiao H. Metformin actions on the liver: Protection mechanisms emerging in hepatocytes and immune cells against nash-related hcc. Int J Mol Sci 2021; 22(9): 5016.
[http://dx.doi.org/10.3390/ijms22095016] [PMID: 34065108]
[89]
Tsogas FK, Majerczyk D, Hart PC. Possible role of metformin as an immune modulator in the tumor microenvironment of ovarian cancer. Int J Mol Sci 2021; 22(2): 867.
[http://dx.doi.org/10.3390/ijms22020867] [PMID: 33467127]
[90]
Kang J, Li C, Gao X, Liu Z, Chen C, Luo D. Metformin inhibits tumor growth and affects intestinal flora in diabetic tumor-bearing mice. Eur J Pharmacol 2021; 912: 174605.
[http://dx.doi.org/10.1016/j.ejphar.2021.174605] [PMID: 34757071]
[91]
Wu Z, Zhang C, Najafi M. Targeting of the tumor immune microenvironment by metformin. J Cell Commun Signal 2021.
[http://dx.doi.org/10.1007/s12079-021-00648-w] [PMID: 34611852]
[92]
Bahrambeigi S, Shafiei-Irannejad V. Immune-mediated anti-tumor effects of metformin; targeting metabolic reprogramming of T cells as a new possible mechanism for anti-cancer effects of metformin. Biochem Pharmacol 2020; 174: 113787.
[http://dx.doi.org/10.1016/j.bcp.2019.113787] [PMID: 31884044]
[93]
Munoz LE, Huang L, Bommireddy R, et al. Metformin reduces PD-L1 on tumor cells and enhances the anti-tumor immune response generated by vaccine immunotherapy. J Immunother Cancer 2021; 9(11): e002614.
[http://dx.doi.org/10.1136/jitc-2021-002614] [PMID: 34815353]
[94]
Cabello P, Pineda B, Tormo E, Lluch A, Eroles P. The antitumor effect of metformin is mediated by mir-26a in breast cancer. Int J Mol Sci 2016; 17(8): 1298.
[http://dx.doi.org/10.3390/ijms17081298] [PMID: 27517917]
[95]
Gao ZY, Liu Z, Bi MH, et al. Metformin induces apoptosis via a mitochondria-mediated pathway in human breast cancer cells in vitro. Exp Ther Med 2016; 11(5): 1700-6.
[http://dx.doi.org/10.3892/etm.2016.3143] [PMID: 27168791]
[96]
Shi B, Hu X, He H, Fang W. Metformin suppresses breast cancer growth via inhibition of cyclooxygenase-2. Oncol Lett 2021; 22(2): 615.
[http://dx.doi.org/10.3892/ol.2021.12876] [PMID: 34257723]
[97]
Chen J, Qin C, Zhou Y, Chen Y, Mao M, Yang J. Metformin may induce ferroptosis by inhibiting autophagy via lncRNA H19 in breast cancer. FEBS Open Bio 2022; 12(1): 146-53.
[http://dx.doi.org/10.1002/2211-5463.13314] [PMID: 34644456]
[98]
Lee JO, Kang MJ, Byun WS, et al. Metformin overcomes resistance to cisplatin in Triple-Negative Breast Cancer (TNBC) cells by targeting RAD51. Breast Cancer Res 2019; 21(1): 115.
[http://dx.doi.org/10.1186/s13058-019-1204-2] [PMID: 31640742]
[99]
Qian W, Li J, Chen K, et al. Metformin suppresses tumor angiogenesis and enhances the chemosensitivity of gemcitabine in a genetically engineered mouse model of pancreatic cancer. Life Sci 2018; 208: 253-61.
[http://dx.doi.org/10.1016/j.lfs.2018.07.046] [PMID: 30053447]
[100]
Soliman GA, Shukla SK, Etekpo A, et al. The synergistic effect of an atp-competitive inhibitor of mtor and metformin on pancreatic tumor growth. Curr Dev Nutr 2020; 4(9): nzaa131.
[http://dx.doi.org/10.1093/cdn/nzaa131] [PMID: 32908958]
[101]
Vitali E, Boemi I, Piccini S, et al. A novel insight into the anticancer mechanism of metformin in pancreatic neuroendocrine tumor cells. Mol Cell Endocrinol 2020; 509: 110803.
[http://dx.doi.org/10.1016/j.mce.2020.110803] [PMID: 32251713]
[102]
Nair V, Sreevalsan S, Basha R, et al. Mechanism of metformin-dependent inhibition of mammalian target of rapamycin (mTOR) and Ras activity in pancreatic cancer: Role of specificity protein (Sp) transcription factors. J Biol Chem 2014; 289(40): 27692-701.
[http://dx.doi.org/10.1074/jbc.M114.592576] [PMID: 25143389]
[103]
Bhat M, Yanagiya A, Graber T, et al. Metformin requires 4E-BPs to induce apoptosis and repress translation of Mcl-1 in hepatocellular carcinoma cells. Oncotarget 2017; 8(31): 50542-56.
[http://dx.doi.org/10.18632/oncotarget.10671] [PMID: 28881582]
[104]
Wu H, Sun Y, Tao C, et al. Metformin induces apoptosis of human hepatocellular carcinoma HepG2 cells by activating an AMPK/p53/miR-23a/FOXA1 pathway. OncoTargets Ther 2016; 9: 2845-53.
[http://dx.doi.org/10.2147/OTT.S99770] [PMID: 27274280]
[105]
Yamashita T, Kato K, Fujihara S, et al. Anti-diabetic drug metformin inhibits cell proliferation and tumor growth in gallbladder cancer via G0/G1 cell cycle arrest. Anticancer Drugs 2020; 31(3): 231-40.
[http://dx.doi.org/10.1097/CAD.0000000000000870] [PMID: 31815765]
[106]
Podhorecka M. Metformin - its anti-cancer effects in hematologic malignancies. Oncol Rev 2021; 15(1): 514.
[http://dx.doi.org/10.4081/oncol.2021.514] [PMID: 33747367]
[107]
Veeramachaneni R, Yu W, Newton JM, et al. Metformin generates profound alterations in systemic and tumor immunity with associated antitumor effects. J Immunother Cancer 2021; 9(7): e002773.
[http://dx.doi.org/10.1136/jitc-2021-002773] [PMID: 34230113]
[108]
Di Francesco AM, Toesca A, Cenciarelli C, Giordano A, Gasbarrini A, Puglisi MA. Metabolic modification in gastrointestinal cancer stem cells: Characteristics and therapeutic approaches. J Cell Physiol 2016; 231(10): 2081-7.
[http://dx.doi.org/10.1002/jcp.25318] [PMID: 26791139]
[109]
Mayer MJ, Klotz LH, Venkateswaran V. Metformin and prostate cancer stem cells: A novel therapeutic target. Prostate Cancer Prostatic Dis 2015; 18(4): 303-9.
[http://dx.doi.org/10.1038/pcan.2015.35] [PMID: 26215782]
[110]
Saini N, Yang X. Metformin as an anti-cancer agent: Actions and mechanisms targeting cancer stem cells. Acta Biochim Biophys Sin 2018; 50(2): 133-43.
[http://dx.doi.org/10.1093/abbs/gmx106] [PMID: 29342230]
[111]
Liu Q, Tong D, Liu G, et al. Metformin inhibits prostate cancer progression by targeting tumor-associated inflammatory infiltration. Clin Cancer Res 2018; 24(22): 5622-34.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-0420] [PMID: 30012567]
[112]
Li B, Zhou P, Xu K, et al. Metformin induces cell cycle arrest, apoptosis and autophagy through ROS/JNK signaling pathway in human osteosarcoma. Int J Biol Sci 2020; 16(1): 74-84.
[http://dx.doi.org/10.7150/ijbs.33787] [PMID: 31892847]
[113]
Khodaei F, Hosseini SM, Omidi M, Hosseini SF, Rezaei M. Cytotoxicity of metformin against HT29 colon cancer cells contributes to mitochondrial Sirt3 upregulation. J Biochem Mol Toxicol 2021; 35(3): e22662.
[http://dx.doi.org/10.1002/jbt.22662] [PMID: 33147367]
[114]
Gandini S, Puntoni M, Heckman-Stoddard BM, et al. Metformin and cancer risk and mortality: A systematic review and meta-analysis taking into account biases and confounders. Cancer Prev Res 2014; 7(9): 867-85.
[http://dx.doi.org/10.1158/1940-6207.CAPR-13-0424] [PMID: 24985407]
[115]
Saraei P, Asadi I, Kakar MA, Moradi-Kor N. The beneficial effects of metformin on cancer prevention and therapy: A comprehensive review of recent advances. Cancer Manag Res 2019; 11: 3295-313.
[http://dx.doi.org/10.2147/CMAR.S200059] [PMID: 31114366]
[116]
Kim YS, Choi EA, Lee J, et al. Metformin use reduced the overall risk of cancer in diabetic patients: A study based on the Korean NHIS-HEALS cohort. Nutr Metab Cardiovasc Dis 2020; 30(10): 1714-22.
[http://dx.doi.org/10.1016/j.numecd.2020.05.010] [PMID: 32753274]
[117]
Kuo YJ, Sung FC, Hsieh PF, Chang HP, Wu KL, Wu HC. Metformin reduces prostate cancer risk among men with benign prostatic hyperplasia: A nationwide population‐based cohort study. Cancer Med 2019; 8(5): 2514-23.
[http://dx.doi.org/10.1002/cam4.2025] [PMID: 30968600]
[118]
Joshua AM, Zannella VE, Downes MR, et al. A pilot ‘window of opportunity’ neoadjuvant study of metformin in localised prostate cancer. Prostate Cancer Prostatic Dis 2014; 17(3): 252-8.
[http://dx.doi.org/10.1038/pcan.2014.20] [PMID: 24861559]
[119]
Shin HS, Sun HJ, Whang YM, Park YJ, Park DJ, Cho SW. Metformin reduces thyroid cancer tumor growth in the metastatic niche of bone by inhibiting osteoblastic rankl productions. Thyroid 2021; 31(5): 760-71.
[http://dx.doi.org/10.1089/thy.2019.0851] [PMID: 32791889]
[120]
Cao X, Wen ZS, Wang XD, Li Y, Liu KY, Wang X. The clinical effect of metformin on the survival of lung cancer patients with diabetes: A comprehensive systematic review and meta-analysis of retrospective studies. J Cancer 2017; 8(13): 2532-41.
[http://dx.doi.org/10.7150/jca.19750] [PMID: 28900491]
[121]
Col NF, Ochs L, Springmann V, Aragaki AK, Chlebowski RT. Metformin and breast cancer risk: A meta-analysis and critical literature review. Breast Cancer Res Treat 2012; 135(3): 639-46.
[http://dx.doi.org/10.1007/s10549-012-2170-x] [PMID: 22847511]
[122]
Aksoy S, Sendur MAN, Altundag K. Demographic and clinico-pathological characteristics in patients with invasive breast cancer receiving metformin. Med Oncol 2013; 30(2): 590.
[http://dx.doi.org/10.1007/s12032-013-0590-z] [PMID: 23636908]
[123]
Xu H, Chen K, Jia X, et al. Metformin use is associated with better survival of breast cancer patients with diabetes: A meta-analysis. Oncologist 2015; 20(11): 1236-44.
[http://dx.doi.org/10.1634/theoncologist.2015-0096] [PMID: 26446233]
[124]
Hadad SM, Coates P, Jordan LB, et al. Evidence for biological effects of metformin in operable breast cancer: Biomarker analysis in a pre-operative window of opportunity randomized trial. Breast Cancer Res Treat 2015; 150(1): 149-55.
[http://dx.doi.org/10.1007/s10549-015-3307-5] [PMID: 25682077]
[125]
Ko KP, Ma SH, Yang JJ, et al. Metformin intervention in obese non-diabetic patients with breast cancer: Phase II randomized, double-blind, placebo-controlled trial. Breast Cancer Res Treat 2015; 153(2): 361-70.
[http://dx.doi.org/10.1007/s10549-015-3519-8] [PMID: 26293146]
[126]
Soliman PT, Zhang Q, Broaddus RR, et al. Prospective evaluation of the molecular effects of metformin on the endometrium in women with newly diagnosed endometrial cancer: A window of opportunity study. Gynecol Oncol 2016; 143(3): 466-71.
[http://dx.doi.org/10.1016/j.ygyno.2016.10.011] [PMID: 27745917]
[127]
Mitsuhashi A, Kiyokawa T, Sato Y, Shozu M. Effects of metformin on endometrial cancer cell growth in vivo: A preoperative prospective trial. Cancer 2014; 120(19): 2986-95.
[http://dx.doi.org/10.1002/cncr.28853] [PMID: 24917306]
[128]
Laskov I, Drudi L, Beauchamp MC, et al. Anti-diabetic doses of metformin decrease proliferation markers in tumors of patients with endometrial cancer. Gynecol Oncol 2014; 134(3): 607-14.
[http://dx.doi.org/10.1016/j.ygyno.2014.06.014] [PMID: 24972190]
[129]
Li L, Wang L, Li J, et al. Metformin-induced reduction of cd39 and cd73 blocks myeloid-derived suppressor cell activity in patients with ovarian cancer. Cancer Res 2018; 78(7): 1779-91.
[http://dx.doi.org/10.1158/0008-5472.CAN-17-2460] [PMID: 29374065]
[130]
Tseng CH. Metformin use and cervical cancer risk in female patients with type 2 diabetes. Oncotarget 2016; 7(37): 59548-55.
[http://dx.doi.org/10.18632/oncotarget.10934] [PMID: 27486978]
[131]
Meng F, Song L, Wang W. Metformin improves overall survival of colorectal cancer patients with diabetes: A meta-analysis. J Diabetes Res 2017; 2017: 1-8.
[http://dx.doi.org/10.1155/2017/5063239] [PMID: 28271076]
[132]
Roshan MHK, Shing YK, Pace NP. Metformin as an adjuvant in breast cancer treatment. SAGE Open Med 2019; 7: 1-16.
[http://dx.doi.org/10.1177/2050312119865114] [PMID: 31360518]
[133]
Zannella VE, Dal Pra A, Muaddi H, et al. Reprogramming metabolism with metformin improves tumor oxygenation and radiotherapy response. Clin Cancer Res 2013; 19(24): 6741-50.
[http://dx.doi.org/10.1158/1078-0432.CCR-13-1787] [PMID: 24141625]
[134]
Bragagnoli AC, Araujo RLC, Ferraz MW, et al. Metformin plus lrinotecan in patients with refractory colorectal cancer: A phase 2 clinical trial. Br J Cancer 2021; 124(6): 1072-8.
[http://dx.doi.org/10.1038/s41416-020-01208-6] [PMID: 33398062]
[135]
Lee J, Choi EA, Kim YS, et al. Metformin usage and the risk of colorectal cancer: A national cohort study. Int J Colorectal Dis 2021; 36(2): 303-10.
[http://dx.doi.org/10.1007/s00384-020-03765-x] [PMID: 32968891]
[136]
Hosono K, Endo H, Takahashi H, et al. Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer Prev Res 2010; 3(9): 1077-83.
[http://dx.doi.org/10.1158/1940-6207.CAPR-10-0186] [PMID: 20810669]
[137]
Higurashi T, Hosono K, Takahashi H, et al. Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: A multicentre double-blind, placebo-controlled, randomised phase 3 trial. Lancet Oncol 2016; 17(4): 475-83.
[http://dx.doi.org/10.1016/S1470-2045(15)00565-3] [PMID: 26947328]
[138]
Sadeghi N, Abbruzzese JL, Yeung SCJ, Hassan M, Li D. Metformin use is associated with better survival of diabetic patients with pancreatic cancer. Clin Cancer Res 2012; 18(10): 2905-12.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-2994] [PMID: 22465831]
[139]
Wang S, Lin Y, Xiong X, et al. Low-dose metformin reprograms the tumor immune microenvironment in human esophageal cancer: Results of a phase ii clinical trial. Clin Cancer Res 2020; 26(18): 4921-32.
[http://dx.doi.org/10.1158/1078-0432.CCR-20-0113] [PMID: 32646922]
[140]
Buchbinder EI, Desai A. CTLA-4 and PD-1 Pathways. Am J Clin Oncol 2016; 39(1): 98-106.
[http://dx.doi.org/10.1097/COC.0000000000000239] [PMID: 26558876]
[141]
Scharping NE, Menk AV, Whetstone RD, Zeng X, Delgoffe GM. Efficacy of pd-1 blockade is potentiated by metformin-induced reduction of tumor hypoxia. Cancer Immunol Res 2017; 5(1): 9-16.
[http://dx.doi.org/10.1158/2326-6066.CIR-16-0103] [PMID: 27941003]
[142]
Afzal MZ, Mercado RR, Shirai K. Efficacy of metformin in combination with immune checkpoint inhibitors (anti-PD-1/anti-CTLA-4) in metastatic malignant melanoma. J Immunother Cancer 2018; 6(1): 64.
[http://dx.doi.org/10.1186/s40425-018-0375-1] [PMID: 29966520]
[143]
Zeng Y, Guo T, Zhou Y, et al. Clinical outcomes of advanced non-small cell lung cancer patients harboring distinct subtypes of EGFR mutations and receiving first-line tyrosine kinase inhibitors: Brain metastasis and de novo T790M matters. BMC Cancer 2022; 22(1): 198.
[http://dx.doi.org/10.1186/s12885-022-09245-5] [PMID: 35189835]
[144]
Lu T, Li M, Zhao M, et al. Metformin inhibits human non-small cell lung cancer by regulating AMPK–CEBPB–PDL1 signaling pathway. Cancer Immunol Immunother 2022; 71(7): 1733-46.
[http://dx.doi.org/10.1007/s00262-021-03116-x] [PMID: 34837101]
[145]
Han Y, Li CW, Hsu JM, et al. Metformin reverses PARP inhibitors-induced epithelial-mesenchymal transition and PD-L1 upregulation in triple-negative breast cancer. Am J Cancer Res 2019; 9(4): 800-15.
[PMID: 31106005]
[146]
Yin X, Han S, Song C, et al. Metformin enhances gefitinib efficacy by interfering with interactions between tumor-associated macrophages and head and neck squamous cell carcinoma cells. Cell Oncol 2019; 42(4): 459-75.
[http://dx.doi.org/10.1007/s13402-019-00446-y] [PMID: 31001733]
[147]
Hamieh L, McKay RR, Lin X, Moreira RB, Simantov R, Choueiri TK. Effect of metformin use on survival outcomes in patients with metastatic renal cell carcinoma. Clin Genitourin Cancer 2017; 15(2): 221-9.
[http://dx.doi.org/10.1016/j.clgc.2016.06.017] [PMID: 27460432]
[148]
Memmott RM, Mercado JR, Maier CR, Kawabata S, Fox SD, Dennis PA. Metformin prevents tobacco carcinogen--induced lung tumorigenesis. Cancer Prev Res 2010; 3(9): 1066-76.
[http://dx.doi.org/10.1158/1940-6207.CAPR-10-0055] [PMID: 20810672]
[149]
Algire C, Amrein L, Bazile M, David S, Zakikhani M, Pollak M. Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo. Oncogene 2011; 30(10): 1174-82.
[http://dx.doi.org/10.1038/onc.2010.483] [PMID: 21102522]
[150]
Fujita Y, Inagaki N. Metformin: New preparations and nonglycemic benefits. Curr Diab Rep 2017; 17(1): 5.
[http://dx.doi.org/10.1007/s11892-017-0829-8] [PMID: 28116648]
[151]
Mirazi N, Shoaei J, Khazaei A, Hosseini A. A comparative study on effect of metformin and metformin-conjugated nanotubes on blood glucose homeostasis in diabetic rats. Eur J Drug Metab Pharmacokinet 2015; 40(3): 343-8.
[http://dx.doi.org/10.1007/s13318-014-0213-x] [PMID: 24969688]
[152]
Arrieta O, Barrón F, Padilla MÁS, et al. Effect of metformin plus tyrosine kinase inhibitors compared with tyrosine kinase inhibitors alone in patients with epidermal growth factor receptor-mutated lung adenocarcinoma: A phase 2 randomized clinical trial. JAMA Oncol 2019; 5(11): e192553.
[http://dx.doi.org/10.1001/jamaoncol.2019.2553] [PMID: 31486833]
[153]
Li L, Jiang L, Wang Y, et al. Combination of metformin and gefitinib as first-line therapy for nondiabetic advanced nsclc patients with egfr mutations: A randomized, double-blind phase ii trial. Clin Cancer Res 2019; 25(23): 6967-75.
[http://dx.doi.org/10.1158/1078-0432.CCR-19-0437] [PMID: 31413010]
[154]
Arrieta O, Zatarain-Barrón ZL, Turcott JG, et al. Association of bmi with benefit of metformin plus epidermal growth factor receptor-tyrosine kinase inhibitors in patients with advanced lung adenocarcinoma: A secondary analysis of a phase 2 randomized clinical trial. JAMA Oncol 2022; 8(3): 477-9.
[http://dx.doi.org/10.1001/jamaoncol.2021.7015] [PMID: 35024769]
[155]
Yendamuri S, Barbi J, Pabla S, et al. Body mass index influences the salutary effects of metformin on survival after lobectomy for stage i nsclc. J Thorac Oncol 2019; 14(12): 2181-7.
[http://dx.doi.org/10.1016/j.jtho.2019.07.020] [PMID: 31398539]
[156]
Knouff C, Auwerx J. Peroxisome proliferator-activated receptor-gamma calls for activation in moderation: Lessons from genetics and pharmacology. Endocr Rev 2004; 25(6): 899-918.
[http://dx.doi.org/10.1210/er.2003-0036] [PMID: 15583022]
[157]
Zhu Y, Qi C, Korenberg JR, et al. Structural organization of mouse peroxisome proliferator-activated receptor gamma (mPPAR gamma) gene: Alternative promoter use and different splicing yield two mPPAR gamma isoforms. Proc Natl Acad Sci 1995; 92(17): 7921-5.
[http://dx.doi.org/10.1073/pnas.92.17.7921] [PMID: 7644514]
[158]
Engwa G, Nwalo F, Chiezey V, Unachukwu M, Ojo O, Ubi B. Assessment of the pro12ala polymorphism in the ppar-gamma2 gene among type 2 diabetes patients in a Nigerian population. J Clin Med 2018; 7(4): 69.
[http://dx.doi.org/10.3390/jcm7040069] [PMID: 29621178]
[159]
Altshuler D, Hirschhorn JN, Klannemark M, et al. The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 2000; 26(1): 76-80.
[http://dx.doi.org/10.1038/79216] [PMID: 10973253]
[160]
Yao L, Li K, Zhang L, Yao S, Piao Z, Song L. Influence of the Pro12Ala polymorphism of PPAR-γ on age at onset and sRAGE levels in Alzheimer’s disease. Brain Res 2009; 1291: 133-9.
[http://dx.doi.org/10.1016/j.brainres.2009.07.034] [PMID: 19631630]
[161]
Schwanstecher C, Meyer U, Schwanstecher M. K(IR)6.2 polymorphism predisposes to type 2 diabetes by inducing overactivity of pancreatic beta-cell ATP-sensitive K(+) channels. Diabetes 2002; 51(3): 875-9.
[http://dx.doi.org/10.2337/diabetes.51.3.875] [PMID: 11872696]
[162]
Li Y. The KCNJ11 E23K gene polymorphism and type 2 diabetes mellitus in the Chinese Han population: A meta-analysis of 6,109 subjects. Mol Biol Rep 2013; 40(1): 141-6.
[http://dx.doi.org/10.1007/s11033-012-2042-9] [PMID: 23054005]

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