{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T02:32:50Z","timestamp":1784860370281,"version":"3.55.0"},"reference-count":120,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2018,2,1]],"date-time":"2018-02-01T00:00:00Z","timestamp":1517443200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Regulatory Toxicology and Pharmacology"],"published-print":{"date-parts":[[2018,2]]},"DOI":"10.1016\/j.yrtph.2017.12.023","type":"journal-article","created":{"date-parts":[[2017,12,30]],"date-time":"2017-12-30T07:40:42Z","timestamp":1514619642000},"page":"324-332","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":74,"special_numbering":"C","title":["A reappraisal on metformin"],"prefix":"10.1016","volume":"92","author":[{"given":"Tu\u011fba","family":"Adak","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afshin","family":"Samadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ay\u015fe Zeynep","family":"\u00dcnal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9702-4214","authenticated-orcid":false,"given":"Suna","family":"Sabuncuo\u011flu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"issue":"8","key":"10.1016\/j.yrtph.2017.12.023_bib1","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.2337\/dc16-2368","article-title":"Is it time to change the type 2 diabetes treatment Paradigm? Yes! GLP-1 RAs should replace metformin in the type 2 diabetes algorithm","volume":"40","author":"Abdul-Ghani","year":"2017","journal-title":"Diabetes Care"},{"issue":"10","key":"10.1016\/j.yrtph.2017.12.023_bib2","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1038\/onc.2010.483","article-title":"Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo","volume":"30","author":"Algire","year":"2011","journal-title":"Oncogene"},{"issue":"1","key":"10.1016\/j.yrtph.2017.12.023_bib3","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1677\/JOE-08-0278","article-title":"Metformin induces oxidative stress in white adipocytes and raises uncoupling protein 2 levels","volume":"199","author":"Anedda","year":"2008","journal-title":"J. Endocrinol."},{"key":"10.1016\/j.yrtph.2017.12.023_bib4","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.brainresbull.2016.02.005","article-title":"Neuroprotective effects of metformin against Abeta-mediated inhibition of long-term potentiation in rats fed a high-fat diet","volume":"121","author":"Asadbegi","year":"2016","journal-title":"Brain Res. Bull."},{"issue":"8","key":"10.1016\/j.yrtph.2017.12.023_bib5","doi-asserted-by":"crossref","first-page":"553","DOI":"10.2337\/diacare.12.8.553","article-title":"Traditional plant medicines as treatments for diabetes","volume":"12","author":"Bailey","year":"1989","journal-title":"Diabetes Care"},{"key":"10.1016\/j.yrtph.2017.12.023_bib6","first-page":"115","article-title":"Metformin: its botanical background","volume":"21","author":"Bailey","year":"2004","journal-title":"Perit. Dial. Int."},{"issue":"11","key":"10.1016\/j.yrtph.2017.12.023_bib7","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1111\/dom.12354","article-title":"Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls","volume":"16","author":"Bannister","year":"2014","journal-title":"Diabetes Obes. Metabol."},{"issue":"4","key":"10.1016\/j.yrtph.2017.12.023_bib8","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1038\/tpj.2009.15","article-title":"Genetic variation in the organic cation transporter 1 is associated with metformin response in patients with diabetes mellitus","volume":"9","author":"Becker","year":"2009","journal-title":"Pharmacogenomics J."},{"key":"10.1016\/j.yrtph.2017.12.023_bib9","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1186\/s12885-015-1719-6","article-title":"No evidence for a decreased risk of thyroid cancer in association with use of metformin or other antidiabetic drugs: a case-control study","volume":"15","author":"Becker","year":"2015","journal-title":"BMC Canc."},{"issue":"25","key":"10.1016\/j.yrtph.2017.12.023_bib10","doi-asserted-by":"crossref","first-page":"3576","DOI":"10.1038\/sj.onc.1211024","article-title":"The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level","volume":"27","author":"Ben Sahra","year":"2008","journal-title":"Oncogene"},{"issue":"21","key":"10.1016\/j.yrtph.2017.12.023_bib11","doi-asserted-by":"crossref","first-page":"2593","DOI":"10.1200\/JCO.2011.39.3769","article-title":"Dual effect of metformin on breast cancer proliferation in a randomized presurgical trial","volume":"30","author":"Bonanni","year":"2012","journal-title":"J. Clin. Oncol. : offi. J. Am. Soc. Clin. Oncol."},{"issue":"14","key":"10.1016\/j.yrtph.2017.12.023_bib12","doi-asserted-by":"crossref","first-page":"6745","DOI":"10.1158\/0008-5472.CAN-06-4447","article-title":"Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth","volume":"67","author":"Buzzai","year":"2007","journal-title":"Canc. Res."},{"issue":"7","key":"10.1016\/j.yrtph.2017.12.023_bib13","doi-asserted-by":"crossref","first-page":"e0133349","DOI":"10.1371\/journal.pone.0133349","article-title":"Metformin induced AMPK activation, g0\/g1 phase cell cycle arrest and the inhibition of growth of esophageal squamous cell carcinomas in vitro and in vivo","volume":"10","author":"Cai","year":"2015","journal-title":"PLos One"},{"key":"10.1016\/j.yrtph.2017.12.023_bib14","series-title":"Research Society for the Study of Diabetes in India. RSSDI Textbook of Diabetes Mellitus","author":"Chandalia","year":"2012"},{"key":"10.1016\/j.yrtph.2017.12.023_bib15","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1186\/s12913-015-1139-y","article-title":"Cost-effectiveness of dapagliflozin versus DPP-4 inhibitors as an add-on to metformin in the treatment of type 2 diabetes mellitus from a UK healthcare system perspective","volume":"15","author":"Charokopou","year":"2015","journal-title":"BMC Health Serv. Res."},{"issue":"7556","key":"10.1016\/j.yrtph.2017.12.023_bib16","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/522265a","article-title":"Anti-ageing pill pushed as bona fide drug","volume":"522","author":"Check Hayden","year":"2015","journal-title":"Nature"},{"key":"10.1016\/j.yrtph.2017.12.023_bib17","series-title":"Proceedings of the National Academy of Sciences of the United States of America","first-page":"3907","article-title":"Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription","volume":"106","author":"Chen","year":"2009"},{"key":"10.1016\/j.yrtph.2017.12.023_bib18","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1097\/FPC.0b013e32833fe789","article-title":"Role of organic cation transporter 3 (SLC22A3) and its missense variants in the pharmacologic action of metformin","volume":"20","author":"Chen","year":"2010","journal-title":"Pharmacogenetics Genom."},{"key":"10.1016\/j.yrtph.2017.12.023_bib19","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.neuropharm.2015.07.023","article-title":"Antidiabetic drugs restore abnormal transport of amyloid-beta across the blood-brain barrier and memory impairment in db\/db mice","volume":"101","author":"Chen","year":"2016","journal-title":"Neuropharmacology"},{"issue":"1","key":"10.1016\/j.yrtph.2017.12.023_bib20","article-title":"Statins and finasteride use differentially modify the impact of metformin on prostate cancer incidence in men with type 2 diabetes","volume":"1","author":"Chen-Pin","year":"2014","journal-title":"Annals of translational medicine & epidemiology"},{"key":"10.1016\/j.yrtph.2017.12.023_bib21","series-title":"xPharm: the Comprehensive Pharmacology Reference","first-page":"1","article-title":"Metformin","author":"Day","year":"2007"},{"issue":"2","key":"10.1016\/j.yrtph.2017.12.023_bib22","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/s00228-013-1604-7","article-title":"The effect of lansoprazole, an OCT inhibitor, on metformin pharmacokinetics in healthy subjects","volume":"70","author":"Ding","year":"2014","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"10.1016\/j.yrtph.2017.12.023_bib23","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1741-7015-9-33","article-title":"Understanding the benefit of metformin use in cancer treatment","volume":"9","author":"Dowling","year":"2011","journal-title":"BMC Med."},{"issue":"3","key":"10.1016\/j.yrtph.2017.12.023_bib24","doi-asserted-by":"crossref","first-page":"R31","DOI":"10.1530\/JME-12-0007","article-title":"Metformin in cancer: translational challenges","volume":"48","author":"Dowling","year":"2012","journal-title":"J. Mol. Endocrinol."},{"key":"10.1016\/j.yrtph.2017.12.023_bib25","unstructured":"Drugbank, Metformin, 2016. Available from: https:\/\/www.drugbank.ca\/drugs\/DB00331. Accessed January,16, 2016."},{"key":"10.1016\/j.yrtph.2017.12.023_bib26","unstructured":"Drugscom. Metformin side effects, 2016. Available from: https:\/\/www.drugs.com\/sfx\/metformin-side-effects.html. Accessed March 12, 2017."},{"issue":"7503","key":"10.1016\/j.yrtph.2017.12.023_bib27","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1136\/bmj.38415.708634.F7","article-title":"Metformin and reduced risk of cancer in diabetic patients","volume":"330","author":"Evans","year":"2005","journal-title":"BMJ (Clin. Res. ed)"},{"key":"10.1016\/j.yrtph.2017.12.023_bib28","series-title":"Proceedings of the National Academy of Sciences of the United States of America","first-page":"9066","article-title":"Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity","volume":"110","author":"Everard","year":"2013"},{"key":"10.1016\/j.yrtph.2017.12.023_bib29","series-title":"Analogue-based Drug Discovery II","year":"2010"},{"issue":"2","key":"10.1016\/j.yrtph.2017.12.023_bib30","doi-asserted-by":"crossref","first-page":"81","DOI":"10.2165\/11534750-000000000-00000","article-title":"Clinical pharmacokinetics of metformin","volume":"50","author":"Graham","year":"2011","journal-title":"Clin. Pharmacokinet."},{"issue":"6","key":"10.1016\/j.yrtph.2017.12.023_bib31","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1016\/j.neuropharm.2011.01.033","article-title":"Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer's-like changes","volume":"60","author":"Gupta","year":"2011","journal-title":"Neuropharmacology"},{"issue":"3","key":"10.1016\/j.yrtph.2017.12.023_bib32","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1007\/s10549-011-1612-1","article-title":"Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial","volume":"128","author":"Hadad","year":"2011","journal-title":"Breast Canc. Res. Treat."},{"issue":"6254","key":"10.1016\/j.yrtph.2017.12.023_bib33","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1126\/science.349.6254.1274","article-title":"A Trial for the ages","volume":"349","author":"Hall","year":"2015","journal-title":"Science (New York, NY)"},{"issue":"4","key":"10.1016\/j.yrtph.2017.12.023_bib34","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/j.cell.2009.03.016","article-title":"Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein","volume":"137","author":"He","year":"2009","journal-title":"Cell"},{"issue":"4","key":"10.1016\/j.yrtph.2017.12.023_bib35","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.ajog.2010.01.035","article-title":"Role of human placental apical membrane transporters in the efflux of glyburide, rosiglitazone, and metformin","volume":"202","author":"Hemauer","year":"2010","journal-title":"Am. J. Obstet. Gynecol."},{"key":"10.1016\/j.yrtph.2017.12.023_bib36","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1007\/BF02000097","article-title":"Die wirkung des biguanids und seiner derivate aud den zuckerstoffwechsel","volume":"142","author":"Hesse","year":"1929","journal-title":"Arch Exp Path Pharmacol"},{"key":"10.1016\/j.yrtph.2017.12.023_bib37","doi-asserted-by":"crossref","first-page":"81","DOI":"10.25100\/cm.v42i1.754","article-title":"Bioavalaibility and pharmacokinetic comparison of two formulations of metformin 850 mg tablets in healthy Colombian volunteers","volume":"42","author":"Holgu\u00edn","year":"2011","journal-title":"Colomb. M\u00e9d."},{"issue":"6","key":"10.1016\/j.yrtph.2017.12.023_bib38","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1111\/jdi.12328","article-title":"New mechanisms of metformin action: focusing on mitochondria and the gut","volume":"6","author":"Hur","year":"2015","journal-title":"Journal of diabetes investigation"},{"key":"10.1016\/j.yrtph.2017.12.023_bib39","unstructured":"IDF Diabetes Atlas, 2017. Available from: http:\/\/www.diabetesatlas.org\/. Accessed April 19."},{"issue":"4","key":"10.1016\/j.yrtph.2017.12.023_bib40","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1007\/s11883-016-0568-3","article-title":"Metformin: an old therapy that deserves a new indication for the treatment of obesity","volume":"18","author":"Igel","year":"2016","journal-title":"Curr. Atherosclerosis Rep."},{"issue":"5","key":"10.1016\/j.yrtph.2017.12.023_bib41","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1111\/j.1532-5415.2012.03916.x","article-title":"Metformin, other antidiabetic drugs, and risk of Alzheimer's disease: a population-based case-control study","volume":"60","author":"Imfeld","year":"2012","journal-title":"J. Am. Geriatr. Soc."},{"issue":"1","key":"10.1016\/j.yrtph.2017.12.023_bib42","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1124\/jpet.109.163642","article-title":"Potent and specific inhibition of mMate1-mediated efflux of type I organic cations in the liver and kidney by pyrimethamine","volume":"333","author":"Ito","year":"2010","journal-title":"J. Pharmacol. Exp. Therapeut."},{"issue":"2","key":"10.1016\/j.yrtph.2017.12.023_bib43","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1124\/jpet.111.184986","article-title":"Competitive inhibition of the luminal efflux by multidrug and toxin extrusions, but not basolateral uptake by organic cation transporter 2, is the likely mechanism underlying the pharmacokinetic drug-drug interactions caused by cimetidine in the kidney","volume":"340","author":"Ito","year":"2012","journal-title":"J. Pharmacol. Exp. Therapeut."},{"issue":"13","key":"10.1016\/j.yrtph.2017.12.023_bib44","doi-asserted-by":"crossref","first-page":"2369","DOI":"10.1016\/j.ejca.2010.06.012","article-title":"Metformin: taking away the candy for cancer?","volume":"46","author":"Jalving","year":"2010","journal-title":"Eur. J. Canc."},{"issue":"3","key":"10.1016\/j.yrtph.2017.12.023_bib45","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.molcel.2005.03.027","article-title":"AMP-activated protein kinase induces a p53-dependent metabolic checkpoint","volume":"18","author":"Jones","year":"2005","journal-title":"Mol. Cell"},{"issue":"5","key":"10.1016\/j.yrtph.2017.12.023_bib46","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.cmet.2010.03.014","article-title":"Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner","volume":"11","author":"Kalender","year":"2010","journal-title":"Cell Metabol."},{"key":"10.1016\/j.yrtph.2017.12.023_bib47","doi-asserted-by":"crossref","first-page":"6839735","DOI":"10.1155\/2016\/6839735","article-title":"Effects of liraglutide combined with short-term continuous subcutaneous insulin infusion on glycemic control and beta cell function in patients with newly diagnosed type 2 diabetes mellitus: a pilot study","volume":"2016","author":"Ke","year":"2016","journal-title":"J. Diabetes Res."},{"key":"10.1016\/j.yrtph.2017.12.023_bib48","series-title":"Proceedings of the National Academy of Sciences of the United States of America","first-page":"21830","article-title":"Biguanide metformin acts on tau phosphorylation via mTOR\/protein phosphatase 2A (PP2A) signaling","volume":"107","author":"Kickstein","year":"2010"},{"issue":"7","key":"10.1016\/j.yrtph.2017.12.023_bib49","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1124\/dmd.113.055616","article-title":"Effects of proton pump inhibitors on metformin pharmacokinetics and pharmacodynamics","volume":"42","author":"Kim","year":"2014","journal-title":"Drug Metabol. Dispos."},{"issue":"2","key":"10.1016\/j.yrtph.2017.12.023_bib50","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1007\/s12032-011-9846-7","article-title":"Metformin and cancer: new applications for an old drug","volume":"29","author":"Kourelis","year":"2012","journal-title":"Med. Oncol."},{"issue":"6","key":"10.1016\/j.yrtph.2017.12.023_bib51","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1038\/clpt.2011.36","article-title":"Effects of a MATE protein inhibitor, pyrimethamine, on the renal elimination of metformin at oral microdose and at therapeutic dose in healthy subjects","volume":"89","author":"Kusuhara","year":"2011","journal-title":"Clin. Pharmacol. Therapeut."},{"issue":"19","key":"10.1016\/j.yrtph.2017.12.023_bib52","doi-asserted-by":"crossref","first-page":"5935","DOI":"10.1128\/AEM.01357-14","article-title":"Effect of metformin on metabolic improvement and gut microbiota","volume":"80","author":"Lee","year":"2014","journal-title":"Appl. Environ. Microbiol."},{"key":"10.1016\/j.yrtph.2017.12.023_bib53","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/978-3-642-38007-5_21","article-title":"New perspective for an old antidiabetic drug: metformin as anticancer agent","volume":"159","author":"Leone","year":"2014","journal-title":"Canc. Treat Res."},{"issue":"4","key":"10.1016\/j.yrtph.2017.12.023_bib54","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1111\/j.1753-0407.2011.00119.x","article-title":"Metformin as an antitumor agent in cancer prevention and treatment","volume":"3","author":"Li","year":"2011","journal-title":"J. Diabetes"},{"key":"10.1016\/j.yrtph.2017.12.023_bib55","doi-asserted-by":"crossref","unstructured":"Long-term safety, Tolerability, and weight loss associated with metformin in the diabetes prevention Program outcomes study. Diabetes Care. 2012;35(4):731\u2013737.","DOI":"10.2337\/dc11-1299"},{"key":"10.1016\/j.yrtph.2017.12.023_bib56","doi-asserted-by":"crossref","first-page":"636927","DOI":"10.1155\/2013\/636927","article-title":"Risk of cancer in diabetes: the effect of metformin","volume":"2013","author":"Malek","year":"2013","journal-title":"ISRN Endocrinol."},{"key":"10.1016\/j.yrtph.2017.12.023_bib57","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.phrs.2016.12.003","article-title":"A story of metformin-butyrate synergism to control various pathological conditions as a consequence of gut microbiome modification: genesis of a wonder drug?","volume":"117","author":"Maniar","year":"2017","journal-title":"Pharmacol. Res."},{"key":"10.1016\/j.yrtph.2017.12.023_bib58","series-title":"Handbook of Pharmacogenomics and Stratified Medicine","first-page":"683","article-title":"Chapter 30-pharmacogenomics of oral antidiabetic drugs a2-padmanabhan, sandosh","author":"Manolopoulos","year":"2014"},{"issue":"1","key":"10.1016\/j.yrtph.2017.12.023_bib59","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/0021-9150(88)90299-7","article-title":"The antidiabetic drug metformin decreases cholesterol metabolism in cultured human fibroblasts","volume":"71","author":"Maziere","year":"1988","journal-title":"Atherosclerosis"},{"issue":"3","key":"10.1016\/j.yrtph.2017.12.023_bib60","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1007\/s00125-015-3844-9","article-title":"Metformin and the gastrointestinal tract","volume":"59","author":"McCreight","year":"2016","journal-title":"Diabetologia"},{"issue":"12","key":"10.1016\/j.yrtph.2017.12.023_bib61","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1007\/s11886-015-0671-z","article-title":"Impact of gut microbiota on obesity, diabetes, and cardiovascular disease risk","volume":"17","author":"Miele","year":"2015","journal-title":"Curr. Cardiol. Rep."},{"issue":"10","key":"10.1016\/j.yrtph.2017.12.023_bib62","doi-asserted-by":"crossref","first-page":"2981","DOI":"10.2337\/dc13-0229","article-title":"Increased risk of cognitive impairment in patients with diabetes is associated with metformin","volume":"36","author":"Moore","year":"2013","journal-title":"Diabetes Care"},{"key":"10.1016\/j.yrtph.2017.12.023_bib63","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1007\/BF01862957","article-title":"Pharmacology of galegin","volume":"125","author":"Muller","year":"1927","journal-title":"Arch Exp Path Pharmacol"},{"key":"10.1016\/j.yrtph.2017.12.023_bib64","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1016\/j.bcp.2005.09.011","article-title":"Drug specificity and intestinal membrane localization of human organic cation transporters (OCT)","volume":"70","author":"Muller","year":"2005","journal-title":"Biochem. Pharmacol."},{"issue":"5","key":"10.1016\/j.yrtph.2017.12.023_bib65","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1093\/humupd\/dmv025","article-title":"Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis","volume":"21","author":"Naderpoor","year":"2015","journal-title":"Hum. Reprod. Update"},{"key":"10.1016\/j.yrtph.2017.12.023_bib66","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/BF01263443","article-title":"Biguanides","volume":"14","author":"Nattrass","year":"1978","journal-title":"Diabetologia"},{"key":"10.1016\/j.yrtph.2017.12.023_bib67","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1002\/hep.23103","article-title":"Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver","volume":"50","author":"Nies","year":"2009","journal-title":"Hepatology"},{"issue":"7","key":"10.1016\/j.yrtph.2017.12.023_bib68","doi-asserted-by":"crossref","first-page":"e22163","DOI":"10.1371\/journal.pone.0022163","article-title":"Proton pump inhibitors inhibit metformin uptake by organic cation transporters (OCTs)","volume":"6","author":"Nies","year":"2011","journal-title":"PLos One"},{"key":"10.1016\/j.yrtph.2017.12.023_bib69","series-title":"Proceedings of the National Academy of Sciences of the United States of America","first-page":"17923","article-title":"A human transporter protein that mediates the final excretion step for toxic organic cations","volume":"102","author":"Otsuka","year":"2005"},{"issue":"1","key":"10.1016\/j.yrtph.2017.12.023_bib70","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1210\/er.2008-0030","article-title":"Evidence-based and potential benefits of metformin in the polycystic ovary syndrome: a comprehensive review","volume":"30","author":"Palomba","year":"2009","journal-title":"Endocr. Rev."},{"key":"10.1016\/j.yrtph.2017.12.023_bib71","series-title":"Le galega dans le traitement du diabete","author":"Parturier","year":"1935"},{"key":"10.1016\/j.yrtph.2017.12.023_bib72","first-page":"1","article-title":"Effect of metformin on clinical, metabolic and endocrine outcomes in women with polycystic ovary syndrome: a meta-analysis of randomized controlled trials","author":"Patel","year":"2017","journal-title":"Curr. Med. Res. Opin."},{"issue":"8","key":"10.1016\/j.yrtph.2017.12.023_bib73","doi-asserted-by":"crossref","first-page":"2590","DOI":"10.2337\/db13-1367","article-title":"Metformin pharmacogenomics: current status and future directions","volume":"63","author":"Pawlyk","year":"2014","journal-title":"Diabetes"},{"issue":"12","key":"10.1016\/j.yrtph.2017.12.023_bib74","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1038\/onc.2012.181","article-title":"Targeting metabolism for cancer treatment and prevention: metformin, an old drug with multi-faceted effects","volume":"32","author":"Pierotti","year":"2013","journal-title":"Oncogene"},{"issue":"3","key":"10.1016\/j.yrtph.2017.12.023_bib75","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/nrc3215","article-title":"The insulin and insulin-like growth factor receptor family in neoplasia: an update","volume":"12","author":"Pollak","year":"2012","journal-title":"Nat. Rev. Canc."},{"issue":"1","key":"10.1016\/j.yrtph.2017.12.023_bib76","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1158\/1078-0432.CCR-11-0998","article-title":"The insulin receptor\/insulin-like growth factor receptor family as a therapeutic target in oncology","volume":"18","author":"Pollak","year":"2012","journal-title":"Clin. Canc. Res. : Offi. J Am. Assoc. Canc. Res."},{"issue":"9","key":"10.1016\/j.yrtph.2017.12.023_bib77","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1158\/2159-8290.CD-12-0263","article-title":"Investigating metformin for cancer prevention and treatment: the end of the beginning","volume":"2","author":"Pollak","year":"2012","journal-title":"Canc. Discov."},{"issue":"9","key":"10.1016\/j.yrtph.2017.12.023_bib78","doi-asserted-by":"crossref","first-page":"3693","DOI":"10.1172\/JCI67232","article-title":"Potential applications for biguanides in oncology","volume":"123","author":"Pollak","year":"2013","journal-title":"J. Clin. Invest."},{"issue":"29","key":"10.1016\/j.yrtph.2017.12.023_bib79","doi-asserted-by":"crossref","first-page":"3869","DOI":"10.1200\/JCO.2010.33.7006","article-title":"Randomized trial of tamoxifen versus combined tamoxifen and octreotide LAR Therapy in the adjuvant treatment of early-stage breast cancer in postmenopausal women: NCIC CTG MA.14","volume":"29","author":"Pritchard","year":"2011","journal-title":"J. Clin. Oncol. : Offi. J Am. Soc. Clin. Oncol."},{"issue":"4","key":"10.1016\/j.yrtph.2017.12.023_bib80","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.3390\/metabo3041051","article-title":"Metformin: on ongoing journey across diabetes, cancer therapy and prevention","volume":"3","author":"Pulito","year":"2013","journal-title":"Metabolites"},{"issue":"9","key":"10.1016\/j.yrtph.2017.12.023_bib81","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.1007\/s00125-013-2991-0","article-title":"Molecular mechanism of action of metformin: old or new insights?","volume":"56","author":"Rena","year":"2013","journal-title":"Diabetologia"},{"issue":"1","key":"10.1016\/j.yrtph.2017.12.023_bib82","doi-asserted-by":"crossref","first-page":"109","DOI":"10.4239\/wjd.v6.i1.109","article-title":"\u03b2-cell dysfunction: its critical role in prevention and management of type 2 diabetes","volume":"6","author":"Saisho","year":"2015","journal-title":"World J. Diabetes"},{"issue":"1","key":"10.1016\/j.yrtph.2017.12.023_bib83","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1042\/BJ20061520","article-title":"Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade","volume":"403","author":"Sanders","year":"2007","journal-title":"Biochem. J."},{"issue":"7","key":"10.1016\/j.yrtph.2017.12.023_bib84","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1016\/j.bcp.2008.07.005","article-title":"Transcellular transport of organic cations in double-transfected MDCK cells expressing human organic cation transporters hOCT1\/hMATE1 and hOCT2\/hMATE1","volume":"76","author":"Sato","year":"2008","journal-title":"Biochem. Pharmacol."},{"issue":"1","key":"10.1016\/j.yrtph.2017.12.023_bib85","first-page":"27","article-title":"Effectiveness of metformin on weight loss in non-diabetic individuals with obesity","volume":"121","author":"Seifarth","year":"2013","journal-title":"Exp. Clin. Endocrinol. Diabetes : Offi. J. Ger. Soc. Endocrinol. Ger. Diabetes Assoc."},{"issue":"3","key":"10.1016\/j.yrtph.2017.12.023_bib86","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1111\/jdi.12208","article-title":"Cancer biology in diabetes","volume":"5","author":"Sen","year":"2014","journal-title":"Journal of diabetes investigation"},{"issue":"2","key":"10.1016\/j.yrtph.2017.12.023_bib87","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.ccr.2012.12.008","article-title":"LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin","volume":"23","author":"Shackelford","year":"2013","journal-title":"Canc. Cell"},{"issue":"5754","key":"10.1016\/j.yrtph.2017.12.023_bib88","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.1126\/science.1120781","article-title":"The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin","volume":"310","author":"Shaw","year":"2005","journal-title":"Science (New York, NY)"},{"issue":"5","key":"10.1016\/j.yrtph.2017.12.023_bib89","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1136\/gutjnl-2012-303839","article-title":"An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice","volume":"63","author":"Shin","year":"2014","journal-title":"Gut"},{"issue":"5","key":"10.1016\/j.yrtph.2017.12.023_bib90","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1172\/JCI30558","article-title":"Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action","volume":"117","author":"Shu","year":"2007","journal-title":"J. Clin. Invest."},{"key":"10.1016\/j.yrtph.2017.12.023_bib91","doi-asserted-by":"crossref","first-page":"814896","DOI":"10.1155\/2015\/814896","article-title":"In vitro and in vivo effects of metformin on osteopontin expression in mice adipose-derived multipotent stromal cells and adipose tissue","volume":"2015","author":"Smieszek","year":"2015","journal-title":"J. Diabetes Res."},{"issue":"1","key":"10.1016\/j.yrtph.2017.12.023_bib92","doi-asserted-by":"crossref","DOI":"10.1136\/bmjdrc-2014-000049","article-title":"Metformin and breast and gynecological cancer risk among women with diabetes","volume":"3","author":"Soffer","year":"2015","journal-title":"BMJ Open Diabetes Res. Care"},{"issue":"8","key":"10.1016\/j.yrtph.2017.12.023_bib93","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1007\/s40262-015-0270-6","article-title":"A comprehensive review of drug-drug interactions with metformin","volume":"54","author":"Stage","year":"2015","journal-title":"Clin. Pharmacokinet."},{"issue":"12","key":"10.1016\/j.yrtph.2017.12.023_bib94","doi-asserted-by":"crossref","first-page":"3101","DOI":"10.1007\/s00125-011-2311-5","article-title":"Metformin activates AMP-activated protein kinase in primary human hepatocytes by decreasing cellular energy status","volume":"54","author":"Stephenne","year":"2011","journal-title":"Diabetologia"},{"issue":"9","key":"10.1016\/j.yrtph.2017.12.023_bib95","doi-asserted-by":"crossref","first-page":"4019","DOI":"10.7314\/APJCP.2014.15.9.4019","article-title":"Cisplatin combined with metformin inhibits migration and invasion of human nasopharyngeal carcinoma cells by regulating E-cadherin and MMP-9","volume":"15","author":"Sun","year":"2014","journal-title":"Asian Pac. J. Cancer Prev. : APJCP"},{"issue":"8","key":"10.1016\/j.yrtph.2017.12.023_bib96","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1080\/03007995.2016.1176013","article-title":"Comparison of acarbose and metformin therapy in newly diagnosed type 2 diabetic patients with overweight and\/or obesity","volume":"32","author":"Sun","year":"2016","journal-title":"Curr. Med. Res. Opin."},{"issue":"23","key":"10.1016\/j.yrtph.2017.12.023_bib97","doi-asserted-by":"crossref","first-page":"10067","DOI":"10.7314\/APJCP.2014.15.23.10067","article-title":"Antiproliferative effect of metformin on the endometrium\u2013a clinical trial","volume":"15","author":"Tabrizi","year":"2014","journal-title":"Asian Pac. J. Cancer Prev. : APJCP"},{"issue":"4","key":"10.1016\/j.yrtph.2017.12.023_bib98","doi-asserted-by":"crossref","first-page":"415","DOI":"10.2217\/14622416.9.4.415","article-title":"Polymorphism in human organic cation transporters and metformin action","volume":"9","author":"Takane","year":"2008","journal-title":"Pharmacogenomics"},{"issue":"2","key":"10.1016\/j.yrtph.2017.12.023_bib99","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.bcp.2007.04.010","article-title":"Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions\/H(+)-organic cation antiporters","volume":"74","author":"Tanihara","year":"2007","journal-title":"Biochem. Pharmacol."},{"issue":"9","key":"10.1016\/j.yrtph.2017.12.023_bib100","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1097\/FPC.0b013e3283561666","article-title":"Association of genetic variation in the organic cation transporters OCT1, OCT2 and multidrug and toxin extrusion 1 transporter protein genes with the gastrointestinal side effects and lower BMI in metformin-treated type 2 diabetes patients","volume":"22","author":"Tarasova","year":"2012","journal-title":"Pharmacogenetics Genom."},{"issue":"6","key":"10.1016\/j.yrtph.2017.12.023_bib101","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1590\/S1806-37132013000600002","article-title":"Metformin synergistically enhances antiproliferative effects of cisplatin and etoposide in NCI-H460 human lung cancer cells","volume":"39","author":"Teixeira","year":"2013","journal-title":"J. Bras. Pneumol. : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia"},{"key":"10.1016\/j.yrtph.2017.12.023_bib102","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1111\/pedi.12473","article-title":"Metformin; a review of its history and future: from lilac to longevity","volume":"18","author":"Thomas","year":"2017","journal-title":"Pediatr. Diabetes"},{"issue":"2","key":"10.1016\/j.yrtph.2017.12.023_bib103","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1095\/biolreprod.110.087023","article-title":"Metformin decreases GnRH- and activin-induced gonadotropin secretion in rat pituitary cells: potential involvement of adenosine 5' monophosphate-activated protein kinase (PRKA)","volume":"84","author":"Tosca","year":"2011","journal-title":"Biol. Reprod."},{"issue":"1","key":"10.1016\/j.yrtph.2017.12.023_bib104","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1124\/jpet.108.147918","article-title":"Involvement of human multidrug and toxin extrusion 1 in the drug interaction between cimetidine and metformin in renal epithelial cells","volume":"329","author":"Tsuda","year":"2009","journal-title":"J. Pharmacol. Exp. Therapeut."},{"issue":"6","key":"10.1016\/j.yrtph.2017.12.023_bib105","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1124\/mol.109.056242","article-title":"Targeted disruption of the multidrug and toxin extrusion 1 (mate1) gene in mice reduces renal secretion of metformin","volume":"75","author":"Tsuda","year":"2009","journal-title":"Mol. Pharmacol."},{"issue":"3","key":"10.1016\/j.yrtph.2017.12.023_bib106","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1038\/clpt.2009.92","article-title":"The effects of genetic polymorphisms in the organic cation transporters OCT1, OCT2, and OCT3 on the renal clearance of metformin","volume":"86","author":"Tzvetkov","year":"2009","journal-title":"Clin. Pharmacol. Therapeut."},{"issue":"6","key":"10.1016\/j.yrtph.2017.12.023_bib107","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1042\/CS20110386","article-title":"Cellular and molecular mechanisms of metformin: an overview","volume":"122","author":"Viollet","year":"2012","journal-title":"Clin. Sci."},{"issue":"2","key":"10.1016\/j.yrtph.2017.12.023_bib108","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1210\/10.1210\/er.2006-0038","article-title":"beta-cell failure in diabetes and preservation by clinical treatment","volume":"28","author":"Wajchenberg","year":"2007","journal-title":"Endocr. Rev."},{"issue":"1","key":"10.1016\/j.yrtph.2017.12.023_bib109","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.stem.2012.03.016","article-title":"Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation","volume":"11","author":"Wang","year":"2012","journal-title":"Cell stem cell"},{"issue":"11","key":"10.1016\/j.yrtph.2017.12.023_bib110","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1056\/NEJMoa1214091","article-title":"Increased oxidative metabolism in the Li-Fraumeni syndrome","volume":"368","author":"Wang","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"10.1016\/j.yrtph.2017.12.023_bib111","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/S0021-9258(18)86579-6","article-title":"Studies in the metabolic changes induced by administration of guanidine bases","volume":"33","author":"Watanabe","year":"1918","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.yrtph.2017.12.023_bib112","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1039\/CT9222101790","article-title":"The preparation of methylguanidine, and of \u03b2\u03b2-dimethylguanidine by the interaction of dicyandiamide, and methylammonium and dimethylammonium chlorides respectively","volume":"121","author":"Werner","year":"1922","journal-title":"J. Chem. Soc. Trans."},{"key":"10.1016\/j.yrtph.2017.12.023_bib113","unstructured":"WHO Diabetes Fact Sheet RN, 2017. Available from: http:\/\/www.who.int\/mediacentre\/factsheets\/fs312\/en\/. Accessed July 10."},{"issue":"8","key":"10.1016\/j.yrtph.2017.12.023_bib114","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1172\/JCI14178","article-title":"The blooming of the French lilac","volume":"108","author":"Witters","year":"2001","journal-title":"J. Clin. Invest."},{"issue":"6","key":"10.1016\/j.yrtph.2017.12.023_bib115","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1634\/theoncologist.2009-0285","article-title":"Obesity and cancer","volume":"15","author":"Wolin","year":"2010","journal-title":"Oncol."},{"key":"10.1016\/j.yrtph.2017.12.023_bib116","unstructured":"World Health Organization Grod, 2017. Available from: http:\/\/apps.who.int\/iris\/bitstream\/10665\/204871\/1\/9789241565257_eng.pdf?ua=1. Accessed April 19."},{"issue":"4","key":"10.1016\/j.yrtph.2017.12.023_bib117","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1586\/erm.10.22","article-title":"Obesity, hyperinsulinemia and breast cancer: novel targets and a novel role for metformin","volume":"10","author":"Wysocki","year":"2010","journal-title":"Expert Rev. Mol. Diagn."},{"issue":"2","key":"10.1016\/j.yrtph.2017.12.023_bib118","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1208\/s12248-013-9460-z","article-title":"Influences of organic cation transporter polymorphisms on the population pharmacokinetics of metformin in healthy subjects","volume":"15","author":"Yoon","year":"2013","journal-title":"AAPS J."},{"key":"10.1016\/j.yrtph.2017.12.023_bib119","first-page":"5","article-title":"Modulation of gut microbiota by berberine and metformin during the treatment of high-fat diet-induced obesity in rats","author":"Zhang","year":"2015","journal-title":"Sci. Rep."},{"key":"10.1016\/j.yrtph.2017.12.023_bib120","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1124\/dmd.107.015495","article-title":"Metformin transport by a newly cloned proton-stimulated organic cation transporter (plasma membrane monoamine transporter) expressed in human intestine","volume":"35","author":"Zhou","year":"2007","journal-title":"Drug Metabol. Dispos."}],"container-title":["Regulatory Toxicology and Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0273230017304105?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0273230017304105?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T15:52:54Z","timestamp":1660233174000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0273230017304105"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,2]]},"references-count":120,"alternative-id":["S0273230017304105"],"URL":"https:\/\/doi.org\/10.1016\/j.yrtph.2017.12.023","relation":{},"ISSN":["0273-2300"],"issn-type":[{"value":"0273-2300","type":"print"}],"subject":[],"published":{"date-parts":[[2018,2]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"A reappraisal on metformin","name":"articletitle","label":"Article Title"},{"value":"Regulatory Toxicology and Pharmacology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.yrtph.2017.12.023","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2018 Elsevier Inc. All rights reserved.","name":"copyright","label":"Copyright"}]}}