{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T05:16:24Z","timestamp":1789276584554,"version":"build-2803163510"},"reference-count":39,"publisher":"American Diabetes Association","issue":"2","license":[{"start":{"date-parts":[[2021,12,3]],"date-time":"2021-12-03T00:00:00Z","timestamp":1638489600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/content\/license"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,2,1]]},"abstract":"<jats:sec>\n                    <jats:title>OBJECTIVE<\/jats:title>\n                    <jats:p>Despite that periodical monitoring of cobalamin (vitamin B12) in metformin-treated patients with diabetes is recommended, cobalamin-associated mortality benefits or risks remain unclear. We investigated the association between cobalamin intake and related biomarkers and mortality risk in adults with diabetes using metformin or not.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                    <jats:p>This study included 3,277 adults with type 2 diabetes from the National Health and Nutrition Examination Survey (NHANES) and followed up until 31 December 2015. Weighted Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for mortality risk.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Among 3,277 participants, 865 all-cause deaths occurred during a median follow-up of 7.02 years. There was no robust relationship between all-cause mortality and serum cobalamin or intake of foods or cobalamin supplements, regardless of metformin treatment (each P \u2265 0.120). The doubling of methylmalonic acid (MMA), a cobalamin-deficiency marker, was significantly associated with higher all-cause (HR 1.31 [95% CI 1.18\u20131.45], P &amp;lt; 0.001) and cardiac (HR 1.38 [95% CI 1.14\u20131.67], P = 0.001) mortality. Cobalamin sensitivity was assessed by the combination of binary B12low\/high and MMAlow\/high (cutoff values: cobalamin 400 pg\/mL, MMA 250 nmol\/L). Patients with decreased cobalamin sensitivity (MMAhighB12high) had the highest mortality risk. The multivariable-adjusted HRs (95% CIs) of all-cause mortality in MMAlowB12low, MMAlowB12high, MMAhighB12low, and MMAhighB12high groups were 1.00 (reference), 0.98 (0.75\u20131.28), 1.49 (1.16\u20131.92), and 1.96 (1.38\u20132.78), respectively. That association was especially significant in metformin nonusers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS<\/jats:title>\n                    <jats:p>Serum and dietary cobalamin were not associated with reduced mortality. Decreased cobalamin sensitivity was significantly associated with all-cause and cardiac mortality, particularly among metformin nonusers.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/dc21-1674","type":"journal-article","created":{"date-parts":[[2021,12,3]],"date-time":"2021-12-03T10:40:27Z","timestamp":1638528027000},"page":"276-284","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":58,"title":["Cobalamin Intake and Related Biomarkers: Examining Associations With Mortality Risk Among Adults With Type 2 Diabetes in NHANES"],"prefix":"10.2337","volume":"45","author":[{"given":"Shanjie","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Harbin, China"},{"name":"The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Harbin, China"},{"name":"The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Harbin, China"},{"name":"The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junchen","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Harbin, China"},{"name":"The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Jiamusi University, Jiamusi, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maoyi","family":"Tian","sequence":"additional","affiliation":[{"name":"School of Public Health, Harbin Medical University, Harbin, China"},{"name":"The George Institute for Global Health, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8635-857X","authenticated-orcid":false,"given":"Shaohong","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Harbin, China"},{"name":"The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2045-8567","authenticated-orcid":false,"given":"Bo","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Harbin, China"},{"name":"The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2021,12,3]]},"reference":[{"key":"2022031310161128600_B1","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/nrendo.2017.151","article-title":"Global aetiology and epidemiology of type 2 diabetes mellitus and its complications","volume":"14","author":"Zheng","year":"2018","journal-title":"Nat Rev Endocrinol"},{"key":"2022031310161128600_B2","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s12933-018-0703-2","article-title":"Diabetes, cardiovascular disease and the microcirculation","volume":"17","author":"Strain","year":"2018","journal-title":"Cardiovasc Diabetol"},{"key":"2022031310161128600_B3","doi-asserted-by":"crossref","first-page":"17040","DOI":"10.1038\/nrdp.2017.40","article-title":"Vitamin B12 deficiency","volume":"3","author":"Green","year":"2017","journal-title":"Nat Rev Dis Primers"},{"key":"2022031310161128600_B4","doi-asserted-by":"crossref","first-page":"27","DOI":"10.3389\/fmolb.2016.00027","article-title":"Biomarkers and algorithms for the diagnosis of vitamin B12 deficiency","volume":"3","author":"Hannibal","year":"2016","journal-title":"Front Mol Biosci"},{"key":"2022031310161128600_B5","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.3390\/nu12071925","article-title":"Low vitamin B12 and lipid metabolism: evidence from pre-clinical and clinical studies","volume":"12","author":"Boachie","year":"2020","journal-title":"Nutrients"},{"key":"2022031310161128600_B6","doi-asserted-by":"crossref","first-page":"S32","DOI":"10.2337\/dc20-S003","article-title":"3. Prevention or delay of type 2 diabetes: Standards of Medical Care in Diabetes-2020","volume":"43","author":"American Diabetes Association","year":"2020","journal-title":"Diabetes Care"},{"key":"2022031310161128600_B7","doi-asserted-by":"crossref","first-page":"2493","DOI":"10.2337\/dc20-1104","article-title":"Risk of anemia with metformin use in type 2 diabetes: a MASTERMIND study","volume":"43","author":"Donnelly","year":"2020","journal-title":"Diabetes Care"},{"key":"2022031310161128600_B8","doi-asserted-by":"crossref","first-page":"e3158","DOI":"10.1002\/dmrr.3158","article-title":"Standards of medical care for type 2 diabetes in China 2019","volume":"35","author":"Jia","year":"2019","journal-title":"Diabetes Metab Res Rev"},{"key":"2022031310161128600_B9","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1111\/pedi.12719","article-title":"ISPAD Clinical practice consensus guidelines 2018: type 2 diabetes mellitus in youth","volume":"19","author":"Zeitler","year":"2018","journal-title":"Pediatr Diabetes"},{"key":"2022031310161128600_B10","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1056\/NEJMoa060900","article-title":"Homocysteine lowering with folic acid and B vitamins in vascular disease","volume":"354","author":"Lonn","year":"2006","journal-title":"N Engl J Med"},{"key":"2022031310161128600_B11","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1016\/j.clnu.2016.10.018","article-title":"A randomized placebo controlled trial of vitamin B12 supplementation to prevent cognitive decline in older diabetic people with borderline low serum vitamin B12","volume":"36","author":"Kwok","year":"2017","journal-title":"Clin Nutr"},{"key":"2022031310161128600_B12","first-page":"CD011906","article-title":"Vitamin and mineral supplementation for maintaining cognitive function in cognitively healthy people in mid and late life","volume":"12","author":"Rutjes","year":"2018","journal-title":"Cochrane Database Syst Rev"},{"key":"2022031310161128600_B13","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s00394-010-0119-6","article-title":"Is a low blood level of vitamin B12 a cardiovascular and diabetes risk factor? A systematic review of cohort studies","volume":"50","author":"Rafnsson","year":"2011","journal-title":"Eur J Nutr"},{"key":"2022031310161128600_B14","doi-asserted-by":"crossref","first-page":"e1919274","DOI":"10.1001\/jamanetworkopen.2019.19274","article-title":"Association of plasma concentration of vitamin B12 with all-cause mortality in the general population in the Netherlands","volume":"3","author":"Flores-Guerrero","year":"2020","journal-title":"JAMA Netw Open"},{"key":"2022031310161128600_B15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3390\/nu9010001","article-title":"Elevated plasma vitamin B12 concentrations are independent predictors of in-hospital mortality in adult patients at nutritional risk","volume":"9","author":"Cappello","year":"2016","journal-title":"Nutrients"},{"key":"2022031310161128600_B16","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.clnu.2011.08.010","article-title":"Increased vitamin B12 levels are associated with mortality in critically ill medical patients","volume":"31","author":"Sviri","year":"2012","journal-title":"Clin Nutr"},{"key":"2022031310161128600_B17","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1093\/ndt\/gfw090","article-title":"Association of serum vitamin B12 and folate with mortality in incident hemodialysis patients","volume":"32","author":"Soohoo","year":"2017","journal-title":"Nephrol Dial Transplant"},{"key":"2022031310161128600_B18","doi-asserted-by":"crossref","first-page":"217","DOI":"10.2337\/dc20-1607","article-title":"Association of maternal folate and vitamin B12 in early pregnancy with gestational diabetes mellitus: a prospective cohort study","volume":"44","author":"Chen","year":"2021","journal-title":"Diabetes Care"},{"key":"2022031310161128600_B19","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":"2022031310161128600_B20","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1038\/ejcn.2014.272","article-title":"Functional cobalamin (vitamin B12) deficiency: role of advanced age and disorders associated with increased oxidative stress","volume":"69","author":"Solomon","year":"2015","journal-title":"Eur J Clin Nutr"},{"key":"2022031310161128600_B21","doi-asserted-by":"crossref","first-page":"604","DOI":"10.7326\/M18-2478","article-title":"Association among dietary supplement use, nutrient intake, and mortality among U.S. adults: a cohort study","volume":"170","author":"Chen","year":"2019","journal-title":"Ann Intern Med"},{"key":"2022031310161128600_B22","doi-asserted-by":"crossref","first-page":"775","DOI":"10.2337\/dc17-1954","article-title":"Increasing mortality in adults with diabetes and low estimated glomerular filtration rate in the absence of albuminuria","volume":"41","author":"Kramer","year":"2018","journal-title":"Diabetes Care"},{"key":"2022031310161128600_B23","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.2337\/dc19-2424","article-title":"Use of antihyperglycemic medications in U.S. adults: an analysis of the National Health and Nutrition Examination Survey","volume":"43","author":"Le","year":"2020","journal-title":"Diabetes Care"},{"key":"2022031310161128600_B24","doi-asserted-by":"crossref","first-page":"2955","DOI":"10.1007\/s00216-014-8148-2","article-title":"An LC-MS\/MS method for serum methylmalonic acid suitable for monitoring vitamin B12 status in population surveys","volume":"407","author":"Mineva","year":"2015","journal-title":"Anal Bioanal Chem"},{"key":"2022031310161128600_B25","doi-asserted-by":"crossref","first-page":"101741","DOI":"10.1016\/j.redox.2020.101741","article-title":"Mitochondria-derived methylmalonic acid, a surrogate biomarker of mitochondrial dysfunction and oxidative stress, predicts all-cause and cardiovascular mortality in the general population","volume":"37","author":"Wang","year":"2020","journal-title":"Redox Biol"},{"key":"2022031310161128600_B26","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1213\/ANE.0000000000002332","article-title":"Bias, confounding, and interaction: lions and tigers, and bears, oh my!","volume":"125","author":"Vetter","year":"2017","journal-title":"Anesth Analg"},{"key":"2022031310161128600_B27","doi-asserted-by":"crossref","first-page":"102526","DOI":"10.1016\/j.ctim.2020.102526","article-title":"Folic acid and vitamin B12 supplementation in subjects with type 2 diabetes mellitus: a multi-arm randomized controlled clinical trial","volume":"53","author":"Satapathy","year":"2020","journal-title":"Complement Ther Med"},{"key":"2022031310161128600_B28","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.diabres.2011.03.016","article-title":"Improving neuropathy scores in type 2 diabetic patients using micronutrients supplementation","volume":"93","author":"Farvid","year":"2011","journal-title":"Diabetes Res Clin Pract"},{"key":"2022031310161128600_B29","doi-asserted-by":"crossref","first-page":"55","DOI":"10.11622\/smedj.2016027","article-title":"Vitamin B supplementation for diabetic peripheral neuropathy","volume":"57","author":"Jayabalan","year":"2016","journal-title":"Singapore Med J"},{"key":"2022031310161128600_B30","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1093\/nutrit\/nuu011","article-title":"Vitamin B12 in meat and dairy products","volume":"73","author":"Gille","year":"2015","journal-title":"Nutr Rev"},{"key":"2022031310161128600_B31","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":"2022031310161128600_B32","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1093\/qjmed\/hcz164","article-title":"Supraphysiological vitamin B12 serum concentrations without supplementation: the pitfalls of interpretation","volume":"113","author":"Vollbracht","year":"2020","journal-title":"QJM"},{"key":"2022031310161128600_B33","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/s41586-020-2630-0","article-title":"Age-induced accumulation of methylmalonic acid promotes tumour progression","volume":"585","author":"Gomes","year":"2020","journal-title":"Nature"},{"key":"2022031310161128600_B34","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1002\/jcsm.12260","article-title":"Vitamin B12 deficiency and impaired expression of amnionless during aging","volume":"9","author":"Pann\u00e9rec","year":"2018","journal-title":"J Cachexia Sarcopenia Muscle"},{"key":"2022031310161128600_B35","doi-asserted-by":"crossref","first-page":"3963","DOI":"10.1007\/s00018-011-0861-9","article-title":"Age-related lysosomal dysfunction: an unrecognized roadblock for cobalamin trafficking?","volume":"68","author":"Zhao","year":"2011","journal-title":"Cell Mol Life Sci"},{"key":"2022031310161128600_B36","doi-asserted-by":"crossref","first-page":"485","DOI":"10.3233\/JAD-2011-101524","article-title":"Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin","volume":"24","author":"Hsu","year":"2011","journal-title":"J Alzheimers Dis"},{"key":"2022031310161128600_B37","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\u2019s disease: a population-based case-control study","volume":"60","author":"Imfeld","year":"2012","journal-title":"J Am Geriatr Soc"},{"key":"2022031310161128600_B38","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1016\/j.bbadis.2018.04.009","article-title":"Mst1 inhibits Sirt3 expression and contributes to diabetic cardiomyopathy through inhibiting Parkin-dependent mitophagy","volume":"1865","author":"Wang","year":"2019","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"2022031310161128600_B39","doi-asserted-by":"crossref","first-page":"101517","DOI":"10.1016\/j.redox.2020.101517","article-title":"Mechanisms of action of metformin in type 2 diabetes: effects on mitochondria and leukocyte-endothelium interactions","volume":"34","author":"Apostolova","year":"2020","journal-title":"Redox Biol"}],"container-title":["Diabetes Care"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/diabetesjournals.org\/care\/article-pdf\/45\/2\/276\/642551\/dc211674.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/care\/article-pdf\/45\/2\/276\/642551\/dc211674.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,13]],"date-time":"2022-03-13T07:25:58Z","timestamp":1647156358000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/care\/article\/45\/2\/276\/139016\/Cobalamin-Intake-and-Related-Biomarkers-Examining"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,3]]},"references-count":39,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,12,3]]},"published-print":{"date-parts":[[2022,2,1]]}},"URL":"https:\/\/doi.org\/10.2337\/dc21-1674","relation":{"has-preprint":[{"id-type":"doi","id":"10.2337\/figshare.16965025.v1","asserted-by":"object"},{"id-type":"doi","id":"10.2337\/figshare.16965025","asserted-by":"object"}]},"ISSN":["0149-5992"],"issn-type":[{"value":"0149-5992","type":"print"}],"subject":[],"published":{"date-parts":[[2021,12,3]]}}}