{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T05:09:05Z","timestamp":1793250545127,"version":"4.5.0"},"reference-count":40,"publisher":"Elsevier BV","issue":"2","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\/"}],"funder":[{"DOI":"10.13039\/100009947","name":"Merck Sharp & Dohme","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009947","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004191","name":"Novo Nordisk","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004191","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["clinicalkey.fr","clinicalkey.jp","clinicalkey.es","clinicalkey.com.au","clinicalkey.com","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Journal of Diabetes and its Complications"],"published-print":{"date-parts":[[2018,2]]},"DOI":"10.1016\/j.jdiacomp.2017.11.001","type":"journal-article","created":{"date-parts":[[2017,11,8]],"date-time":"2017-11-08T06:30:32Z","timestamp":1510122632000},"page":"171-178","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":70,"title":["Long-term treatment with metformin in type 2 diabetes and methylmalonic acid: Post hoc analysis of a randomized controlled 4.3 year trial"],"prefix":"10.1016","volume":"32","author":[{"given":"Mattijs","family":"Out","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriaan","family":"Kooy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Lehert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Casper A.","family":"Schalkwijk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coen D.A.","family":"Stehouwer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0005","doi-asserted-by":"crossref","first-page":"S64","DOI":"10.2337\/dc17-S011","article-title":"8. Pharmacologic approaches to glycemic treatment","volume":"40","author":"American Diabetes Association","year":"2017","journal-title":"Diabetes Care"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0010","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1016\/S0140-6736(98)07037-8","volume":"352","year":"1998","journal-title":"Lancet"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0015","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1001\/archinternmed.2009.20","article-title":"Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus","volume":"169","author":"Kooy","year":"2009","journal-title":"Arch Intern Med"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0020","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/nrendo.2013.256","article-title":"Metformin\u2014mode of action and clinical implications for diabetes and cancer","volume":"10","author":"Pernicova","year":"2014","journal-title":"Nat Rev Endocrinol"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0025","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1210\/jc.2015-3754","article-title":"Long-term metformin use and vitamin B12 deficiency in the diabetes prevention program outcomes study","volume":"101","author":"Aroda","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0030","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.diabet.2016.03.008","article-title":"Association between metformin and vitamin B12 deficiency in patients with type 2 diabetes: a systematic review and meta-analysis","volume":"42","author":"Chapman","year":"2016","journal-title":"Diabete Metab"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0035","doi-asserted-by":"crossref","first-page":"90","DOI":"10.2337\/diaclin.33.2.90","article-title":"Metformin with either histamine H2-receptor antagonists or proton pump inhibitors: a polypharmacy recipe for neuropathy via vitamin B12 depletion","volume":"33","author":"Zdilla","year":"2015","journal-title":"Clin Diabetes"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0040","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1046\/j.1365-2796.2003.01213.x","article-title":"Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial","volume":"254","author":"Wulffele","year":"2003","journal-title":"J Intern Med"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0045","doi-asserted-by":"crossref","first-page":"c2181","DOI":"10.1136\/bmj.c2181","article-title":"Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial","volume":"340","author":"de Jager","year":"2010","journal-title":"BMJ"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0050","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s11940-002-0036-y","article-title":"Peripheral neuropathy due to cobalamin deficiency","volume":"4","author":"Saperstein","year":"2002","journal-title":"Curr Treat Options Neurol"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0055","doi-asserted-by":"crossref","first-page":"393","DOI":"10.4158\/EP.1.6.393","article-title":"Nondiabetic neuropathy in a patient with diabetes","volume":"1","author":"Bell","year":"1995","journal-title":"Endocr Pract"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0060","doi-asserted-by":"crossref","first-page":"156","DOI":"10.2337\/dc09-0606","article-title":"Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy","volume":"33","author":"Wile","year":"2010","journal-title":"Diabetes Care"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0065","doi-asserted-by":"crossref","first-page":"253","DOI":"10.4103\/0022-3859.123143","article-title":"Association of B12 deficiency and clinical neuropathy with metformin use in type 2 diabetes patients","volume":"59","author":"Singh","year":"2013","journal-title":"J Postgrad Med"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0070","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1177\/1474651412454924","article-title":"An observational study of the effect of metformin on B12 status and peripheral neuropathy","volume":"12","author":"Chen","year":"2012","journal-title":"Br J Diab Vasc Dis"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0075","first-page":"386","article-title":"Vitamin B12 deficiency and the lack of its consequences in type 2 diabetes patients using metformin","volume":"71","author":"de Groot-Kamphuis","year":"2013","journal-title":"Neth J Med"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0080","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.jdiacomp.2016.08.025","article-title":"Vitamin B12 deficiency is associated with cardiovascular autonomic neuropathy in patients with type 2 diabetes","volume":"31","author":"Hansen","year":"2017","journal-title":"J Diabetes Complicat"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0085","doi-asserted-by":"crossref","first-page":"3208","DOI":"10.2337\/dc13-0012","article-title":"Impact of glycemic control strategies on the progression of diabetic peripheral neuropathy in the bypass angioplasty revascularization investigation 2 diabetes (BARI 2D) cohort","volume":"36","author":"Pop-Busui","year":"2013","journal-title":"Diabetes Care"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0090","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1056\/NEJMcp1113996","article-title":"Clinical practice. Vitamin B12 deficiency","volume":"368","author":"Stabler","year":"2013","journal-title":"N Engl J Med"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0095","doi-asserted-by":"crossref","first-page":"348S","DOI":"10.3945\/ajcn.111.013441","article-title":"Biomarkers of cobalamin (vitamin B-12) status in the epidemiologic setting: a critical overview of context, applications, and performance characteristics of cobalamin, methylmalonic acid, and holotranscobalamin II","volume":"94","author":"Carmel","year":"2011","journal-title":"Am J Clin Nutr"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0100","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.2337\/diacare.25.12.2133","article-title":"Combination of insulin and metformin in the treatment of type 2 diabetes","volume":"25","author":"Wulffele","year":"2002","journal-title":"Diabetes Care"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0105","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1111\/j.1464-5491.1992.tb01879.x","article-title":"Clinical examination versus neurophysiological examination in the diagnosis of diabetic polyneuropathy","volume":"9","author":"Valk","year":"1992","journal-title":"Diabet Med"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0110","doi-asserted-by":"crossref","first-page":"604","DOI":"10.7326\/0003-4819-150-9-200905050-00006","article-title":"A new equation to estimate glomerular filtration rate","volume":"150","author":"Levey","year":"2009","journal-title":"Ann Intern Med"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0115","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.2337\/diacare.23.9.1227","article-title":"Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin","volume":"23","author":"Bauman","year":"2000","journal-title":"Diabetes Care"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0120","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1097\/MOG.0b013e328358d5b9","article-title":"Proton pump inhibitors: potential adverse effects","volume":"28","author":"Abraham","year":"2012","journal-title":"Curr Opin Gastroenterol"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0125","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1007\/BF00427979","article-title":"Disturbance of intestinal absorption following metformin therapy (observations on the mode of action of biguanides)","volume":"5","author":"Berchtold","year":"1969","journal-title":"Diabetologia"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0130","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1097\/SMJ.0b013e3181ce0e4d","article-title":"Metformin-induced vitamin B12 deficiency presenting as a peripheral neuropathy","volume":"103","author":"Bell","year":"2010","journal-title":"South Med J"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0135","doi-asserted-by":"crossref","first-page":"e75","DOI":"10.1016\/j.diabres.2013.12.054","article-title":"Long term use of metformin leading to vitamin B 12 deficiency","volume":"104","author":"Tung","year":"2014","journal-title":"Diabetes Res Clin Pract"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0140","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1136\/bmj.280.6225.1214","article-title":"Megaloblastic anaemia due to vitamin B12 malabsorption associated with long-term metformin treatment","volume":"280","author":"Callaghan","year":"1980","journal-title":"Br Med J"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0145","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/j.clinbiochem.2010.02.011","article-title":"Metformin induces reductions in plasma cobalamin and haptocorrin bound cobalamin levels in elderly diabetic patients","volume":"43","author":"Leung","year":"2010","journal-title":"Clin Biochem"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0150","first-page":"2475","article-title":"Metformin lowers serum cobalamin without changing other markers of cobalamin status: a study on women with polycystic ovary syndrome","volume":"5","author":"Greibe","year":"2013","journal-title":"Forum Nutr"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0155","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.2337\/dc11-0009","article-title":"Diabetes as a cause of clinically significant functional cobalamin deficiency","volume":"34","author":"Solomon","year":"2011","journal-title":"Diabetes Care"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0160","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1212\/01.wnl.0000336370.51010.a1","volume":"72","author":"England","year":"2009","journal-title":"Neurology"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0165","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1093\/ajcn\/84.6.1406","article-title":"Medical Research Council Cognitive Function and Ageing Study. Methylmalonic acid and cognitive function in the Medical Research Council Cognitive Function and Ageing Study","volume":"84","author":"McCracken","year":"2006","journal-title":"Am J Clin Nutr"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0170","doi-asserted-by":"crossref","first-page":"521","DOI":"10.3109\/00365519709084603","article-title":"Metformin increases total serum homocysteine levels in non-diabetic male patients with coronary heart disease","volume":"57","author":"Carlsen","year":"1997","journal-title":"Scand J Clin Lab Invest"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0175","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1016\/j.biochi.2012.10.028","article-title":"Serum vitamin B12 not reflecting vitamin B12 status in patients with type 2 diabetes","volume":"95","author":"Obeid","year":"2013","journal-title":"Biochimie"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0180","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1016\/j.biochi.2013.02.008","article-title":"Diagnosis and management of clinical and subclinical cobalamin deficiencies: why controversies persist in the age of sensitive metabolic testing","volume":"95","author":"Carmel","year":"2013","journal-title":"Biochimie"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0185","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.amjmed.2012.06.022","article-title":"Metanx in type 2 diabetes with peripheral neuropathy: a randomized trial","volume":"126","author":"Fonseca","year":"2013","journal-title":"Am J Med"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0190","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/S0140-6736(10)60576-4","article-title":"Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial","volume":"376","author":"Ismail-Beigi","year":"2010","journal-title":"Lancet"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0195","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/s12031-007-9002-1","article-title":"Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons","volume":"34","author":"El-Mir","year":"2008","journal-title":"J Mol Neurosci"},{"key":"10.1016\/j.jdiacomp.2017.11.001_bb0200","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1002\/mus.21661","article-title":"Signs and symptoms versus nerve conduction studies to diagnose diabetic sensorimotor polyneuropathy: Cl vs. NPhys trial","volume":"42","author":"Dyck","year":"2010","journal-title":"Muscle Nerve"}],"container-title":["Journal of Diabetes and its Complications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1056872717309807?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1056872717309807?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2022,7,9]],"date-time":"2022-07-09T07:25:12Z","timestamp":1657351512000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1056872717309807"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,2]]},"references-count":40,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2018,2]]}},"alternative-id":["S1056872717309807"],"URL":"https:\/\/doi.org\/10.1016\/j.jdiacomp.2017.11.001","relation":{},"ISSN":["1056-8727"],"issn-type":[{"value":"1056-8727","type":"print"}],"subject":[],"published":{"date-parts":[[2018,2]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Long-term treatment with metformin in type 2 diabetes and methylmalonic acid: Post hoc analysis of a randomized controlled 4.3year trial","name":"articletitle","label":"Article Title"},{"value":"Journal of Diabetes and its Complications","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.jdiacomp.2017.11.001","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2017 Elsevier Inc. All rights reserved.","name":"copyright","label":"Copyright"}]}}