{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T03:15:00Z","timestamp":1791342900215,"version":"4.3.1"},"reference-count":92,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T00:00:00Z","timestamp":1685577600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Vitamin B12 (B12) is an essential cofactor of two important biochemical pathways, the degradation of methylmalonic acid and the synthesis of methionine from homocysteine. Methionine is an important donor of methyl groups for numerous biochemical reactions, including DNA synthesis and gene regulation. Besides hematological abnormalities (megaloblastic anemia or even pancytopenia), a deficiency in B12 may cause neurological symptoms, including symptoms resembling diabetic neuropathy. Although extensively studied, the underlining molecular mechanism for the development of diabetic peripheral neuropathy (DPN) is still unclear. Most studies have found a contribution of oxidative stress in the development of DPN. Detailed immunohistochemical investigations in sural nerve biopsies obtained from diabetic patients with DPN point to an activation of inflammatory pathways induced via elevated advanced glycation end products (AGE), ultimately resulting in increased oxidative stress. Similar results have been found in patients with B12 deficiency, indicating that the observed neural changes in patients with DPN might be caused by cellular B12 deficiency. Since novel results show that B12 exerts intrinsic antioxidative activity in vitro and in vivo, B12 may act as an intracellular, particularly as an intramitochondrial, antioxidant, independent from its classical, well-known cofactor function. These novel findings may provide a rationale for the use of B12 for the treatment of DPN, even in subclinical early states.<\/jats:p>","DOI":"10.3390\/nu15112597","type":"journal-article","created":{"date-parts":[[2023,6,2]],"date-time":"2023-06-02T01:33:54Z","timestamp":1685669634000},"page":"2597","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Clinical Pathobiochemistry of Vitamin B12 Deficiency: Improving Our Understanding by Exploring Novel Mechanisms with a Focus on Diabetic Neuropathy"],"prefix":"10.3390","volume":"15","author":[{"given":"Erwin","family":"Schleicher","sequence":"first","affiliation":[{"name":"Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital of T\u00fcbingen, 72076 T\u00fcbingen, Germany"},{"name":"Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich, German Center for Diabetes Research (DZD), 72076 T\u00fcbingen, Germany"},{"name":"German Center for Diabetes Research (DZD e.V.), 85764 Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0236-8760","authenticated-orcid":false,"given":"Triantafyllos","family":"Didangelos","sequence":"additional","affiliation":[{"name":"Diabetes Center, 1st Propaedeutic Department of Internal Medicine, Medical School, \u201cAHEPA\u201d Hospital, Aristotle University of Thessaloniki, 54621 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evangelia","family":"Kotzakioulafi","sequence":"additional","affiliation":[{"name":"Diabetes Center, 1st Propaedeutic Department of Internal Medicine, Medical School, \u201cAHEPA\u201d Hospital, Aristotle University of Thessaloniki, 54621 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Cegan","sequence":"additional","affiliation":[{"name":"Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, 53210 Pardubice, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Peter","sequence":"additional","affiliation":[{"name":"Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital of T\u00fcbingen, 72076 T\u00fcbingen, Germany"},{"name":"Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich, German Center for Diabetes Research (DZD), 72076 T\u00fcbingen, Germany"},{"name":"German Center for Diabetes Research (DZD e.V.), 85764 Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0584-1138","authenticated-orcid":false,"given":"Konstantinos","family":"Kantartzis","sequence":"additional","affiliation":[{"name":"Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich, German Center for Diabetes Research (DZD), 72076 T\u00fcbingen, Germany"},{"name":"German Center for Diabetes Research (DZD e.V.), 85764 Neuherberg, Germany"},{"name":"Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University of T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1503\/cmaj.1031155","article-title":"Vitamin B12 (cobalamin) deficiency in elderly patients","volume":"171","author":"Andres","year":"2004","journal-title":"Can. Med. Assoc. J."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Vincenti, A., Bertuzzo, L., Limitone, A., D\u2019Antona, G., and Cena, H. (2021). Perspective: Practical approach to preventing subclinical B12 deficiency in elderly population. Nutrients, 13.","DOI":"10.3390\/nu13061913"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1995S","DOI":"10.1093\/jn\/nxy201","article-title":"Biomarkers of nutrition for development (BOND): Vitamin B-12 review","volume":"148","author":"Allen","year":"2018","journal-title":"J. Nutr."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Lin, Q., Li, K., Chen, Y., Xie, J., Wu, C., Cui, C., and Deng, B. (2023). Oxidative stress in diabetic peripheral neuropathy: Pathway and mechanism-based treatment. Mol. Neurobiol., 1\u201321.","DOI":"10.1007\/s12035-023-03342-7"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/s41572-019-0092-1","article-title":"Diabetic neuropathy","volume":"5","author":"Feldman","year":"2019","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"DCCT Group (1995). The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann. Intern. Med., 122, 561.","DOI":"10.7326\/0003-4819-122-8-199504150-00001"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"110","DOI":"10.2337\/dc18-1560","article-title":"Improvement in neuropathy outcomes with normalizing HbA1c in patients with type 2 diabetes","volume":"42","author":"Ishibashi","year":"2019","journal-title":"Diabetes Care"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"416","DOI":"10.2337\/dc17-1144","article-title":"The legacy effect in type 2 diabetes: Impact of early glycemic control on future complications (the diabetes & aging study)","volume":"42","author":"Laiteerapong","year":"2019","journal-title":"Diabetes Care"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1111\/dom.14734","article-title":"Metformin-induced vitamin B12 deficiency can cause or worsen distal symmetrical, autonomic and cardiac neuropathy in the patient with diabetes","volume":"24","author":"Bell","year":"2022","journal-title":"Diabetes Obes. Metab."},{"key":"ref_10","first-page":"e31783","article-title":"The impact of vitamin B12 supplementation on clinical outcomes in patients with diabetic neuropathy: A meta-analysis of randomized controlled trials","volume":"14","author":"Karedath","year":"2022","journal-title":"Cureus"},{"key":"ref_11","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":"ref_12","doi-asserted-by":"crossref","first-page":"13186","DOI":"10.1074\/jbc.R113.458810","article-title":"Navigating the B12 road: Assimilation, delivery, and disorders of cobalamin","volume":"288","author":"Gherasim","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_13","unstructured":"(2023, April 19). Office of Dietary Supplements Vitamin B12 Fact Sheet for Health Professionals, Available online: https:\/\/ods.od.nih.gov\/factsheets\/VitaminB12-HealthProfessional\/#disc."},{"key":"ref_14","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. Prim."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2071","DOI":"10.1038\/ajg.2009.231","article-title":"Reassessment of intrinsic factor and parietal cell autoantibodies in atrophic gastritis with respect to cobalamin deficiency","volume":"104","author":"Lahner","year":"2009","journal-title":"Am. J. Gastroenterol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s00592-014-0597-8","article-title":"Influence of duration and dose of metformin on cobalamin deficiency in type 2 diabetes patients using metformin","volume":"52","author":"Beulens","year":"2015","journal-title":"Acta Diabetol."},{"key":"ref_17","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":"Diabetes Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"916","DOI":"10.4239\/wjd.v12.i7.916","article-title":"Long-term metformin therapy and vitamin B12 deficiency: An association to bear in mind","volume":"12","author":"Infante","year":"2021","journal-title":"WJD"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e17918","DOI":"10.1097\/MD.0000000000017918","article-title":"Association between metformin dose and vitamin B12 deficiency in patients with type 2 diabetes","volume":"98","author":"Kim","year":"2019","journal-title":"Medicine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.1001\/jama.2013.280490","article-title":"Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B 12 deficiency","volume":"310","author":"Lam","year":"2013","journal-title":"JAMA"},{"key":"ref_21","first-page":"1499","article-title":"Evaluation of vitamin B12 monitoring in patients on metformin in urban ambulatory care settings","volume":"17","author":"Longo","year":"2019","journal-title":"Pharm. Pract."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"511S","DOI":"10.1093\/advances\/nmy023","article-title":"Proton pump inhibitors, H2-receptor antagonists, metformin, and vitamin B-12 deficiency: Clinical implications","volume":"9","author":"Miller","year":"2018","journal-title":"Adv. Nutr."},{"key":"ref_23","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":"Kooy","year":"2010","journal-title":"BMJ"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"382","DOI":"10.18433\/J3PK7P","article-title":"Metformin and vitamin B12 deficiency: Where do we stand?","volume":"19","author":"Ahmed","year":"2016","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2452853","DOI":"10.1155\/2017\/2452853","article-title":"Perspectives on peripheral neuropathy as a consequence of metformin-induced vitamin B12 deficiency in T2DM","volume":"2017","author":"Ahmed","year":"2017","journal-title":"Int. J. Endocrinol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"102634","DOI":"10.1016\/j.dsx.2022.102634","article-title":"The efficacy of vitamin B12 supplementation for treating vitamin B12 deficiency and peripheral neuropathy in metformin-treated type 2 diabetes mellitus patients: A systematic review","volume":"16","author":"Pratama","year":"2022","journal-title":"Diabetes Metab. Syndr. Clin. Res. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1002\/jimd.12009","article-title":"Vitamin B12, folate, and the methionine remethylation cycle\u2014Biochemistry, pathways, and regulation","volume":"42","author":"Froese","year":"2019","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"11980","DOI":"10.1074\/jbc.M117.784819","article-title":"Clinical or ATPase domain mutations in ABCD4 disrupt the interaction between the vitamin B12-trafficking proteins ABCD4 and LMBD1","volume":"292","author":"Fettelschoss","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1038\/nchembio.67","article-title":"Adenosyltransferase tailors and delivers coenzyme B12","volume":"4","author":"Padovani","year":"2008","journal-title":"Nat. Chem. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.1021\/acs.accounts.1c00083","article-title":"Redox-linked coordination chemistry directs vitamin B 12 trafficking","volume":"54","author":"Banerjee","year":"2021","journal-title":"Acc. Chem. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1016\/j.molmed.2021.07.002","article-title":"Clinical implications of vitamin B12 as redox-active cofactor","volume":"27","author":"Offringa","year":"2021","journal-title":"Trends Mol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1002\/jimd.12012","article-title":"The clinical presentation of cobalamin-related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways","volume":"42","author":"Huemer","year":"2019","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"E4095","DOI":"10.1073\/pnas.1619582114","article-title":"Folate rescues vitamin B12 depletion-induced inhibition of nuclear thymidylate biosynthesis and genome instability","volume":"114","author":"Palmer","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/S0140-6736(81)90649-8","article-title":"Pathogenesis of subacute combined degeneration: A result of methyl group deficiency","volume":"318","author":"Scott","year":"1981","journal-title":"Lancet"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Boachie, J., Adaikalakoteswari, A., Samavat, J., and Saravanan, P. (2020). Low vitamin B12 and lipid metabolism: Evidence from pre-clinical and clinical studies. Nutrients, 12.","DOI":"10.3390\/nu12071925"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"436","DOI":"10.2337\/db19-0197","article-title":"Understanding diabetic neuropathy\u2014From subclinical nerve lesions to severe nerve fiber deficits: A cross-sectional study in patients with type 2 diabetes and healthy control subjects","volume":"69","author":"Groener","year":"2020","journal-title":"Diabetes"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1007\/s00125-004-1663-5","article-title":"Sural nerve pathology in diabetic patients with minimal but progressive neuropathy","volume":"48","author":"Malik","year":"2005","journal-title":"Diabetologia"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.ncl.2013.02.004","article-title":"Diabetic neuropathy part 1","volume":"31","author":"Pasnoor","year":"2013","journal-title":"Neurol. Clin."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.tins.2013.04.008","article-title":"Novel pathogenic pathways in diabetic neuropathy","volume":"36","author":"Zenker","year":"2013","journal-title":"Trends Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1007\/s10571-011-9675-4","article-title":"Experimental evidence that methylmalonic acid provokes oxidative damage and compromises antioxidant defenses in nerve terminal and striatum of young rats","volume":"31","author":"Fernandes","year":"2011","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1179\/174313206X152564","article-title":"Activation of the RAGE pathway: A general mechanism in the pathogenesis of polyneuropathies?","volume":"29","author":"Haslbeck","year":"2007","journal-title":"Neurol. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1055\/s-2005-865600","article-title":"The AGE\/RAGE\/NF-\u039aB pathway may contribute to the pathogenesis of polyneuropathy in impaired glucose tolerance (IGT)","volume":"113","author":"Haslbeck","year":"2005","journal-title":"Exp. Clin. Endocrinol. Diabetes"},{"key":"ref_43","unstructured":"International Diabetes Federation (2021). IDF Diabetes Atlas, International Diabetes Federation. [10th ed.]."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2337\/db2022-01","article-title":"Diagnosis and treatment of painful diabetic peripheral neuropathy","volume":"2022","author":"Ang","year":"2022","journal-title":"Compendia"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1007\/s00125-020-05085-9","article-title":"Diabetic neuropathy: What does the future hold?","volume":"63","author":"Callaghan","year":"2020","journal-title":"Diabetologia"},{"key":"ref_46","first-page":"3425617","article-title":"Diabetic polyneuropathy in type 2 diabetes mellitus: Inflammation, oxidative stress, and mitochondrial function","volume":"2016","year":"2016","journal-title":"J. Diabetes Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1038\/nrneurol.2014.77","article-title":"Mitotoxicity in distal symmetrical sensory peripheral neuropathies","volume":"10","author":"Bennett","year":"2014","journal-title":"Nat. Rev. Neurol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1016\/j.neuron.2017.02.005","article-title":"New horizons in diabetic neuropathy: Mechanisms, bioenergetics, and pain","volume":"93","author":"Feldman","year":"2017","journal-title":"Neuron"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"9524635","DOI":"10.1155\/2020\/9524635","article-title":"Understanding diabetic neuropathy: Focus on oxidative stress","volume":"2020","author":"Pang","year":"2020","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/bs.irn.2019.05.002","article-title":"Disorders of mitochondrial dynamics in peripheral neuropathy: Clues from hereditary neuropathy and diabetes","volume":"Volume 145","author":"Rumora","year":"2019","journal-title":"International Review of Neurobiology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1172\/JCI18058","article-title":"Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily","volume":"114","author":"Bierhaus","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1097\/SHK.0b013e318186262d","article-title":"Role of TOLL-like receptors 2 and 4 and the receptor for advanced glycation end products in high-mobility group box-1- induced inflammation in vivo","volume":"31","author":"Yang","year":"2009","journal-title":"Shock"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Ramasamy, R., Shekhtman, A., and Schmidt, A.M. (2022). The RAGE\/DIAPH1 signaling axis & implications for the pathogenesis of diabetic complications. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23094579"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Thakur, V., Sadanandan, J., and Chattopadhyay, M. (2020). High-mobility group box 1 protein signaling in painful diabetic neuropathy. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21030881"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2563","DOI":"10.1096\/fj.201800754RR","article-title":"Neuropathology of vitamin B12 deficiency in the Cd320 \u2212\/\u2212 mouse","volume":"33","author":"Arora","year":"2019","journal-title":"FASEB J."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Ahmed, M.A., Muntingh, G., and Rheeder, P. (2016). Vitamin B12 deficiency in metformin-treated type-2 diabetes patients, prevalence and association with peripheral neuropathy. BMC Pharmacol. Toxicol., 17.","DOI":"10.1186\/s40360-016-0088-3"},{"key":"ref_57","first-page":"2536","article-title":"Role of vitamin B12 supplementation on incipient neuropathy in patients with type II diabetes mellitus","volume":"12","author":"Chowdary","year":"2019","journal-title":"Drug Invent. Today"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Didangelos, T., Karlafti, E., Kotzakioulafi, E., Kontoninas, Z., Margaritidis, C., Giannoulaki, P., and Kantartzis, K. (2020). Efficacy and safety of the combination of superoxide dismutase, alpha lipoic acid, vitamin b12, and carnitine for 12 months in patients with diabetic neuropathy. Nutrients, 12.","DOI":"10.3390\/nu12113254"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Didangelos, T., Karlafti, E., Kotzakioulafi, E., Margariti, E., Giannoulaki, P., Batanis, G., Tesfaye, S., and Kantartzis, K. (2021). Vitamin B12 supplementation in diabetic neuropathy: A 1-year, randomized, double-blind, placebo-controlled trial. Nutrients, 13.","DOI":"10.3390\/nu13020395"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Dizaye, K.F., and Sheet, T.A. (2014). Therapeutic effect of pregabalin, vitamin B-groups and their combination on patients with diabetic peripheral poly neuropathy. Middle East J. Fam. Med., 12.","DOI":"10.5742\/MEWFM.2014.92556"},{"key":"ref_61","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":"ref_62","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":"ref_63","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":"Singap. Med. J."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e11390","DOI":"10.1097\/MD.0000000000011390","article-title":"Fasudil combined with methylcobalamin or lipoic acid can improve the nerve conduction velocity in patients with diabetic peripheral neuropathy: A meta-analysis","volume":"97","author":"Jiang","year":"2018","journal-title":"Medicine"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"472","DOI":"10.2169\/internalmedicine.38.472","article-title":"Intravenous methylcobalamin treatment for uremic and diabetic neuropathy in chronic hemodialysis patients","volume":"38","author":"Kuwabara","year":"1999","journal-title":"Intern. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1111\/jdi.12493","article-title":"Effects of acetyl-L-carnitine and methylcobalamin for diabetic peripheral neuropathy: A multicenter, randomized, double-blind, controlled trial","volume":"7","author":"Li","year":"2016","journal-title":"J. Diabetes Investig."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/0303-8467(92)90066-C","article-title":"Effects of methylcobalamin on diabetic neuropathy","volume":"94","author":"Yaqub","year":"1992","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"896511","DOI":"10.3389\/fendo.2022.896511","article-title":"Genomic DNA methylation in diabetic chronic complications in patients with type 2 diabetes mellitus","volume":"13","author":"Wang","year":"2022","journal-title":"Front. Endocrinol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1080\/15592294.2019.1615352","article-title":"Genome-wide DNA methylation profiling of human diabetic peripheral neuropathy in subjects with type 2 diabetes mellitus","volume":"14","author":"Guo","year":"2019","journal-title":"Epigenetics"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1186\/s13148-020-00913-6","article-title":"Genome-wide profiling of DNA methylation and gene expression identifies candidate genes for human diabetic neuropathy","volume":"12","author":"Guo","year":"2020","journal-title":"Clin. Epigenet."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s00401-002-0518-8","article-title":"N \u03b5-carboxymethyllysine in diabetic and non-diabetic polyneuropathies","volume":"104","author":"Haslbeck","year":"2002","journal-title":"Acta Neuropathol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1038\/s41467-020-14729-8","article-title":"Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency","volume":"11","author":"Luciani","year":"2020","journal-title":"Nat Commun."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"15078","DOI":"10.1021\/ja904670x","article-title":"Vitamin B12 and redox homeostasis: Cob(II)alamin reacts with superoxide at rates approaching superoxide dismutase (SOD)","volume":"131","author":"Yun","year":"2009","journal-title":"J. Am. Chem. Soc."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1016\/j.freeradbiomed.2011.05.034","article-title":"Vitamin B12 protects against superoxide-induced cell injury in human aortic endothelial cells","volume":"51","author":"Moreira","year":"2011","journal-title":"Free Radic. Biol. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.ajpath.2017.08.032","article-title":"Cobalamin-associated superoxide scavenging in neuronal cells is a potential mechanism for vitamin B12\u2013Deprivation optic neuropathy","volume":"188","author":"Chan","year":"2018","journal-title":"Am. J. Pathol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.freeradbiomed.2009.04.023","article-title":"A novel role for vitamin B12: Cobalamins are intracellular antioxidants in vitro","volume":"47","author":"Birch","year":"2009","journal-title":"Free Radic. Biol. Med."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"van de Lagemaat, E., de Groot, L., and van den Heuvel, E. (2019). Vitamin B12 in relation to oxidative stress: A systematic review. Nutrients, 11.","DOI":"10.3390\/nu11020482"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1111\/j.1365-2362.2010.02430.x","article-title":"Methylcobalamin effects on diabetic neuropathy and nerve protein kinase C in rats: Methylcobalamin and PKC in diabetic neuropathy","volume":"41","author":"Mizukami","year":"2011","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.mayocpiqo.2019.03.002","article-title":"The many faces of cobalamin (vitamin B12) deficiency","volume":"3","author":"Wolffenbuttel","year":"2019","journal-title":"Mayo Clin. Proc. Innov. Qual. Outcomes"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"359S","DOI":"10.3945\/ajcn.111.013458","article-title":"Holotranscobalamin, a marker of vitamin B-12 status: Analytical aspects and clinical utility","volume":"94","author":"Nexo","year":"2011","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1373\/clinchem.2006.080382","article-title":"Detection of vitamin B12 deficiency in older people by measuring vitamin B12 or the active fraction of vitamin B12, holotranscobalamin","volume":"53","author":"Clarke","year":"2007","journal-title":"Clin. Chem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1002\/mus.26783","article-title":"Nutritional neuropathies","volume":"62","author":"Gwathmey","year":"2020","journal-title":"Muscle Nerve"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1515\/CCLM.2003.227","article-title":"Functional vitamin B12 deficiency and determination of holotranscobalamin in populations at risk","volume":"41","author":"Herrmann","year":"2003","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1186\/s40064-016-2252-z","article-title":"Holotranscobalamin (HoloTC, Active-B12) and herbert\u2019s model for the development of vitamin B12 deficiency: A review and alternative hypothesis","volume":"5","author":"Golding","year":"2016","journal-title":"SpringerPlus"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Risch, M., Meier, D.W., Sakem, B., Escobar, P.M., Risch, C., Nydegger, U., and Risch, L. (2015). Vitamin B12 and folate levels in healthy swiss senior citizens: A prospective study evaluating reference intervals and decision limits. BMC Geriatr., 15.","DOI":"10.1186\/s12877-015-0060-x"},{"key":"ref_86","first-page":"1149","article-title":"A review of the cut-off points for the diagnosis of vitamin B12 deficiency in the general population","volume":"53","author":"Palacios","year":"2015","journal-title":"Clin. Chem. Lab. Med. CCLM"},{"key":"ref_87","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":"ref_88","first-page":"680","article-title":"Causes and early diagnosis of vitamin B12 deficiency","volume":"105","author":"Herrmann","year":"2008","journal-title":"Dtsch. \u00c4rzteblatt Int."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.cca.2021.12.015","article-title":"Reference intervals for plasma vitamin B12 and plasma\/serum methylmalonic acid in Danish children, adults and elderly","volume":"525","author":"Abildgaard","year":"2022","journal-title":"Clin. Chim. Acta"},{"key":"ref_90","unstructured":"Department of Medicine and Geriatrics, Caritas Medical Centre, Shamshuipo, Hong Kong, and Wong, C. (2015). Vitamin B12 deficiency in the elderly: Is it worth screening?. Hong Kong Med. J., 21, 155\u2013164."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1093\/ajcn\/nqab193","article-title":"Associations of atrophic gastritis and proton-pump inhibitor drug use with vitamin B-12 status, and the impact of fortified foods, in older adults","volume":"114","author":"Porter","year":"2021","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1002\/mus.20845","article-title":"Vitamin B12 and methylmalonic acid levels in patients presenting with polyneuropathy","volume":"36","author":"Nardin","year":"2007","journal-title":"Muscle Nerve"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/11\/2597\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:46:58Z","timestamp":1760125618000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/11\/2597"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,1]]},"references-count":92,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["nu15112597"],"URL":"https:\/\/doi.org\/10.3390\/nu15112597","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,1]]}}}