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.

Department of Biological and Biochemical Sciences Faculty of Chemical Technology University of Pardubice 53210 Pardubice Czech Republic

Department of Internal Medicine 4 Division of Endocrinology Diabetology and Nephrology University of Tübingen 72076 Tübingen Germany

Diabetes Center 1st Propaedeutic Department of Internal Medicine Medical School AHEPA Hospital Aristotle University of Thessaloniki 54621 Thessaloniki Greece

German Center for Diabetes Research 85764 Neuherberg Germany

Institute for Clinical Chemistry and Pathobiochemistry Department for Diagnostic Laboratory Medicine University Hospital of Tübingen 72076 Tübingen Germany

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich German Center for Diabetes Research 72076 Tübingen Germany

See more in PubMed

Andres E. Vitamin B12 (cobalamin) deficiency in elderly patients. Can. Med. Assoc. J. 2004;171:251–259. doi: 10.1503/cmaj.1031155. PubMed DOI PMC

Vincenti A., Bertuzzo L., Limitone A., D’Antona G., Cena H. Perspective: Practical approach to preventing subclinical B12 deficiency in elderly population. Nutrients. 2021;13:1913. doi: 10.3390/nu13061913. PubMed DOI PMC

Allen L.H., Miller J.W., de Groot L., Rosenberg I.H., Smith A.D., Refsum H., Raiten D.J. Biomarkers of nutrition for development (BOND): Vitamin B-12 review. J. Nutr. 2018;148:1995S–2027S. doi: 10.1093/jn/nxy201. PubMed DOI PMC

Lin Q., Li K., Chen Y., Xie J., Wu C., Cui C., Deng B. Oxidative stress in diabetic peripheral neuropathy: Pathway and mechanism-based treatment. Mol. Neurobiol. 2023:1–21. doi: 10.1007/s12035-023-03342-7. PubMed DOI

Feldman E.L., Callaghan B.C., Pop-Busui R., Zochodne D.W., Wright D.E., Bennett D.L., Bril V., Russell J.W., Viswanathan V. Diabetic neuropathy. Nat. Rev. Dis. Prim. 2019;5:41. doi: 10.1038/s41572-019-0092-1. PubMed DOI

DCCT Group The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann. Intern. Med. 1995;122:561. doi: 10.7326/0003-4819-122-8-199504150-00001. PubMed DOI

Ishibashi F., Taniguchi M., Kosaka A., Uetake H., Tavakoli M. Improvement in neuropathy outcomes with normalizing HbA1c in patients with type 2 diabetes. Diabetes Care. 2019;42:110–118. doi: 10.2337/dc18-1560. PubMed DOI

Laiteerapong N., Ham S.A., Gao Y., Moffet H.H., Liu J.Y., Huang E.S., Karter A.J. The legacy effect in type 2 diabetes: Impact of early glycemic control on future complications (the diabetes & aging study) Diabetes Care. 2019;42:416–426. doi: 10.2337/dc17-1144. PubMed DOI PMC

Bell D.S.H. Metformin-induced vitamin B12 deficiency can cause or worsen distal symmetrical, autonomic and cardiac neuropathy in the patient with diabetes. Diabetes Obes. Metab. 2022;24:1423–1428. doi: 10.1111/dom.14734. PubMed DOI

Karedath J., Batool S., Arshad A., Khalique S., Raja S., Lal B., Chunchu V.A., Hirani S. The impact of vitamin B12 supplementation on clinical outcomes in patients with diabetic neuropathy: A meta-analysis of randomized controlled trials. Cureus. 2022;14:e31783. doi: 10.7759/cureus.31783. PubMed DOI PMC

Solomon L.R. Functional cobalamin (vitamin B12) deficiency: Role of advanced age and disorders associated with increased oxidative stress. Eur. J. Clin. Nutr. 2015;69:687–692. doi: 10.1038/ejcn.2014.272. PubMed DOI

Gherasim C., Lofgren M., Banerjee R. Navigating the B12 road: Assimilation, delivery, and disorders of cobalamin. J. Biol. Chem. 2013;288:13186–13193. doi: 10.1074/jbc.R113.458810. PubMed DOI PMC

Office of Dietary Supplements Vitamin B12 Fact Sheet for Health Professionals. [(accessed on 19 April 2023)]; Available online: https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/#disc.

Green R., Allen L.H., Bjørke-Monsen A.-L., Brito A., Guéant J.-L., Miller J.W., Molloy A.M., Nexo E., Stabler S., Toh B.-H., et al. Vitamin B12 deficiency. Nat. Rev. Dis. Prim. 2017;3:17040. doi: 10.1038/nrdp.2017.40. PubMed DOI

Lahner E., Norman G.L., Severi C., Encabo S., Shums Z., Vannella L., Fave G.D., Annibale B. Reassessment of intrinsic factor and parietal cell autoantibodies in atrophic gastritis with respect to cobalamin deficiency. Am. J. Gastroenterol. 2009;104:2071–2079. doi: 10.1038/ajg.2009.231. PubMed DOI

Beulens J.W.J., Hart H.E., Kuijs R., Kooijman-Buiting A.M.J., Rutten G.E.H.M. Influence of duration and dose of metformin on cobalamin deficiency in type 2 diabetes patients using metformin. Acta Diabetol. 2015;52:47–53. doi: 10.1007/s00592-014-0597-8. PubMed DOI

Chapman L.E., Darling A.L., Brown J.E. Association between metformin and vitamin B12 deficiency in patients with type 2 diabetes: A systematic review and meta-analysis. Diabetes Metab. 2016;42:316–327. doi: 10.1016/j.diabet.2016.03.008. PubMed DOI

Infante M., Leoni M., Caprio M., Fabbri A. Long-term metformin therapy and vitamin B12 deficiency: An association to bear in mind. WJD. 2021;12:916–931. doi: 10.4239/wjd.v12.i7.916. PubMed DOI PMC

Kim J., Ahn C.W., Fang S., Lee H.S., Park J.S. Association between metformin dose and vitamin B12 deficiency in patients with type 2 diabetes. Medicine. 2019;98:e17918. doi: 10.1097/MD.0000000000017918. PubMed DOI PMC

Lam J.R., Schneider J.L., Zhao W., Corley D.A. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B 12 deficiency. JAMA. 2013;310:2435. doi: 10.1001/jama.2013.280490. PubMed DOI

Longo S.L., Ryan J.M., Sheehan K.B., Reid D.J., Conley M.P., Bouwmeester C.J. Evaluation of vitamin B12 monitoring in patients on metformin in urban ambulatory care settings. Pharm. Pract. 2019;17:1499. doi: 10.18549/PharmPract.2019.3.1499. PubMed DOI PMC

Miller J.W. Proton pump inhibitors, H2-receptor antagonists, metformin, and vitamin B-12 deficiency: Clinical implications. Adv. Nutr. 2018;9:511S–518S. doi: 10.1093/advances/nmy023. PubMed DOI PMC

de Jager J., Kooy A., Lehert P., Wulffele M.G., van der Kolk J., Bets D., Verburg J., Donker A.J.M., Stehouwer C.D.A. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: Randomised placebo controlled trial. BMJ. 2010;340:c2181. doi: 10.1136/bmj.c2181. PubMed DOI PMC

Ahmed M.A. Metformin and vitamin B12 deficiency: Where do we stand? J. Pharm. Pharm. Sci. 2016;19:382. doi: 10.18433/J3PK7P. PubMed DOI

Ahmed M.A., Muntingh G.L., Rheeder P. Perspectives on peripheral neuropathy as a consequence of metformin-induced vitamin B12 deficiency in T2DM. Int. J. Endocrinol. 2017;2017:2452853. doi: 10.1155/2017/2452853. PubMed DOI PMC

Pratama S., Lauren B.C., Wisnu W. 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. Diabetes Metab. Syndr. Clin. Res. Rev. 2022;16:102634. doi: 10.1016/j.dsx.2022.102634. PubMed DOI

Froese D.S., Fowler B., Baumgartner M.R. Vitamin B12, folate, and the methionine remethylation cycle—Biochemistry, pathways, and regulation. J. Inherit. Metab. Dis. 2019;42:673–685. doi: 10.1002/jimd.12009. PubMed DOI

Fettelschoss V., Burda P., Sagné C., Coelho D., De Laet C., Lutz S., Suormala T., Fowler B., Pietrancosta N., Gasnier B., et al. Clinical or ATPase domain mutations in ABCD4 disrupt the interaction between the vitamin B12-trafficking proteins ABCD4 and LMBD1. J. Biol. Chem. 2017;292:11980–11991. doi: 10.1074/jbc.M117.784819. PubMed DOI PMC

Padovani D., Labunska T., Palfey B.A., Ballou D.P., Banerjee R. Adenosyltransferase tailors and delivers coenzyme B12. Nat. Chem. Biol. 2008;4:194–196. doi: 10.1038/nchembio.67. PubMed DOI

Banerjee R., Gouda H., Pillay S. Redox-linked coordination chemistry directs vitamin B 12 trafficking. Acc. Chem. Res. 2021;54:2003–2013. doi: 10.1021/acs.accounts.1c00083. PubMed DOI PMC

Offringa A.K., Bourgonje A.R., Schrier M.S., Deth R.C., van Goor H. Clinical implications of vitamin B12 as redox-active cofactor. Trends Mol. Med. 2021;27:931–934. doi: 10.1016/j.molmed.2021.07.002. PubMed DOI

Huemer M., Baumgartner M.R. The clinical presentation of cobalamin-related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways. J. Inherit. Metab. Dis. 2019;42:686–705. doi: 10.1002/jimd.12012. PubMed DOI

Palmer A.M., Kamynina E., Field M.S., Stover P.J. Folate rescues vitamin B12 depletion-induced inhibition of nuclear thymidylate biosynthesis and genome instability. Proc. Natl. Acad. Sci. USA. 2017;114:E4095–E4102. doi: 10.1073/pnas.1619582114. PubMed DOI PMC

Scott J. Pathogenesis of subacute combined degeneration: A result of methyl group deficiency. Lancet. 1981;318:334–337. doi: 10.1016/S0140-6736(81)90649-8. PubMed DOI

Boachie J., Adaikalakoteswari A., Samavat J., Saravanan P. Low vitamin B12 and lipid metabolism: Evidence from pre-clinical and clinical studies. Nutrients. 2020;12:1925. doi: 10.3390/nu12071925. PubMed DOI PMC

Groener J.B., Jende J.M.E., Kurz F.T., Kender Z., Treede R.-D., Schuh-Hofer S., Nawroth P.P., Bendszus M., Kopf S. Understanding diabetic neuropathy—From subclinical nerve lesions to severe nerve fiber deficits: A cross-sectional study in patients with type 2 diabetes and healthy control subjects. Diabetes. 2020;69:436–447. doi: 10.2337/db19-0197. PubMed DOI

Malik R.A., Tesfaye S., Newrick P.G., Walker D., Rajbhandari S.M., Siddique I., Sharma A.K., Boulton A.J.M., King R.H.M., Thomas P.K., et al. Sural nerve pathology in diabetic patients with minimal but progressive neuropathy. Diabetologia. 2005;48:578–585. doi: 10.1007/s00125-004-1663-5. PubMed DOI

Pasnoor M., Dimachkie M.M., Kluding P., Barohn R.J. Diabetic neuropathy part 1. Neurol. Clin. 2013;31:425–445. doi: 10.1016/j.ncl.2013.02.004. PubMed DOI PMC

Zenker J., Ziegler D., Chrast R. Novel pathogenic pathways in diabetic neuropathy. Trends Neurosci. 2013;36:439–449. doi: 10.1016/j.tins.2013.04.008. PubMed DOI

Fernandes C.G., Borges C.G., Seminotti B., Amaral A.U., Knebel L.A., Eichler P., de Oliveira A.B., Leipnitz G., Wajner M. Experimental evidence that methylmalonic acid provokes oxidative damage and compromises antioxidant defenses in nerve terminal and striatum of young rats. Cell. Mol. Neurobiol. 2011;31:775–785. doi: 10.1007/s10571-011-9675-4. PubMed DOI PMC

Haslbeck K.M., Neundörfer B., Schlötzer-Schrehardt U., Bierhaus A., Schleicher E., Pauli E., Haslbeck M., Hecht M., Nawroth P., Heuss D. Activation of the RAGE pathway: A general mechanism in the pathogenesis of polyneuropathies? Neurol. Res. 2007;29:103–110. doi: 10.1179/174313206X152564. PubMed DOI

Haslbeck K.-M., Schleicher E., Bierhaus A., Nawroth P., Haslbeck M., Neundörfer B., Heuss D. The AGE/RAGE/NF-ΚB pathway may contribute to the pathogenesis of polyneuropathy in impaired glucose tolerance (IGT) Exp. Clin. Endocrinol. Diabetes. 2005;113:288–291. doi: 10.1055/s-2005-865600. PubMed DOI

International Diabetes Federation . IDF Diabetes Atlas. 10th ed. International Diabetes Federation; Brussels, Belgium: 2021.

Pop-Busui R., Ang L., Boulton A., Feldman E., Marcus R., Mizokami-Stout K., Singleton J.R., Ziegler D. Diagnosis and treatment of painful diabetic peripheral neuropathy. Compendia. 2022;2022:1–32. doi: 10.2337/db2022-01. PubMed DOI

Callaghan B.C., Gallagher G., Fridman V., Feldman E.L. Diabetic neuropathy: What does the future hold? Diabetologia. 2020;63:891–897. doi: 10.1007/s00125-020-05085-9. PubMed DOI PMC

Román-Pintos L.M., Villegas-Rivera G., Rodríguez-Carrizalez A.D., Miranda-Díaz A.G., Cardona-Muñoz E.G. Diabetic polyneuropathy in type 2 diabetes mellitus: Inflammation, oxidative stress, and mitochondrial function. J. Diabetes Res. 2016;2016:3425617. doi: 10.1155/2016/3425617. PubMed DOI PMC

Bennett G.J., Doyle T., Salvemini D. Mitotoxicity in distal symmetrical sensory peripheral neuropathies. Nat. Rev. Neurol. 2014;10:326–336. doi: 10.1038/nrneurol.2014.77. PubMed DOI PMC

Feldman E.L., Nave K.-A., Jensen T.S., Bennett D.L.H. New horizons in diabetic neuropathy: Mechanisms, bioenergetics, and pain. Neuron. 2017;93:1296–1313. doi: 10.1016/j.neuron.2017.02.005. PubMed DOI PMC

Pang L., Lian X., Liu H., Zhang Y., Li Q., Cai Y., Ma H., Yu X. Understanding diabetic neuropathy: Focus on oxidative stress. Oxidative Med. Cell. Longev. 2020;2020:9524635. doi: 10.1155/2020/9524635. PubMed DOI PMC

Rumora A.E., Savelieff M.G., Sakowski S.A., Feldman E.L. International Review of Neurobiology. Volume 145. Elsevier; Amsterdam, The Netherlands: 2019. Disorders of mitochondrial dynamics in peripheral neuropathy: Clues from hereditary neuropathy and diabetes; pp. 127–176. PubMed PMC

Bierhaus A., Haslbeck K.-M., Humpert P.M., Liliensiek B., Dehmer T., Morcos M., Sayed A.A.R., Andrassy M., Schiekofer S., Schneider J.G., et al. Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily. J. Clin. Investig. 2004;114:1741–1751. doi: 10.1172/JCI18058. PubMed DOI PMC

van Zoelen M.A., Yang H., Florquin S., Meijers J.C., Akira S., Arnold B., Nawroth P.P., Bierhaus A., Tracey K.J., van der Poll T. 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. Shock. 2009;31:280–284. doi: 10.1097/SHK.0b013e318186262d. PubMed DOI PMC

Ramasamy R., Shekhtman A., Schmidt A.M. The RAGE/DIAPH1 signaling axis & implications for the pathogenesis of diabetic complications. Int. J. Mol. Sci. 2022;23:4579. doi: 10.3390/ijms23094579. PubMed DOI PMC

Thakur V., Sadanandan J., Chattopadhyay M. High-mobility group box 1 protein signaling in painful diabetic neuropathy. Int. J. Mol. Sci. 2020;21:881. doi: 10.3390/ijms21030881. PubMed DOI PMC

Arora K., Sequeira J.M., Alarcon J.M., Wasek B., Arning E., Bottiglieri T., Quadros E.V. Neuropathology of vitamin B12 deficiency in the Cd320 −/− mouse. FASEB J. 2019;33:2563–2573. doi: 10.1096/fj.201800754RR. PubMed DOI PMC

Ahmed M.A., Muntingh G., Rheeder P. Vitamin B12 deficiency in metformin-treated type-2 diabetes patients, prevalence and association with peripheral neuropathy. BMC Pharmacol. Toxicol. 2016;17:44. doi: 10.1186/s40360-016-0088-3. PubMed DOI PMC

Chowdary P.R., Praveen D., Aanandhi M.V. Role of vitamin B12 supplementation on incipient neuropathy in patients with type II diabetes mellitus. Drug Invent. Today. 2019;12:2536–2539.

Didangelos T., Karlafti E., Kotzakioulafi E., Kontoninas Z., Margaritidis C., Giannoulaki P., Kantartzis K. 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. 2020;12:3254. doi: 10.3390/nu12113254. PubMed DOI PMC

Didangelos T., Karlafti E., Kotzakioulafi E., Margariti E., Giannoulaki P., Batanis G., Tesfaye S., Kantartzis K. Vitamin B12 supplementation in diabetic neuropathy: A 1-year, randomized, double-blind, placebo-controlled trial. Nutrients. 2021;13:395. doi: 10.3390/nu13020395. PubMed DOI PMC

Dizaye K.F., Sheet T.A. Therapeutic effect of pregabalin, vitamin B-groups and their combination on patients with diabetic peripheral poly neuropathy. Middle East J. Fam. Med. 2014;12 doi: 10.5742/MEWFM.2014.92556. DOI

Farvid M.S., Homayouni F., Amiri Z., Adelmanesh F. Improving neuropathy scores in type 2 diabetic patients using micronutrients supplementation. Diabetes Res. Clin. Pract. 2011;93:86–94. doi: 10.1016/j.diabres.2011.03.016. PubMed DOI

Fonseca V.A., Lavery L.A., Thethi T.K., Daoud Y., DeSouza C., Ovalle F., Denham D.S., Bottiglieri T., Sheehan P., Rosenstock J. Metanx in type 2 diabetes with peripheral neuropathy: A randomized trial. Am. J. Med. 2013;126:141–149. doi: 10.1016/j.amjmed.2012.06.022. PubMed DOI

Jayabalan B., Low L.L. Vitamin B supplementation for diabetic peripheral neuropathy. Singap. Med. J. 2016;57:55–59. doi: 10.11622/smedj.2016027. PubMed DOI PMC

Jiang D.-Q., Xu L.-C., Jiang L.-L., Li M.-X., Wang Y. Fasudil combined with methylcobalamin or lipoic acid can improve the nerve conduction velocity in patients with diabetic peripheral neuropathy: A meta-analysis. Medicine. 2018;97:e11390. doi: 10.1097/MD.0000000000011390. PubMed DOI PMC

Kuwabara S., Nakazawa R., Azuma N., Suzuki M., Miyajima K., Fukutake T., Hattori T. Intravenous methylcobalamin treatment for uremic and diabetic neuropathy in chronic hemodialysis patients. Intern. Med. 1999;38:472–475. doi: 10.2169/internalmedicine.38.472. PubMed DOI

Li S., Chen X., Li Q., Du J., Liu Z., Peng Y., Xu M., Li Q., Lei M., Wang C., et al. Effects of acetyl-L-carnitine and methylcobalamin for diabetic peripheral neuropathy: A multicenter, randomized, double-blind, controlled trial. J. Diabetes Investig. 2016;7:777–785. doi: 10.1111/jdi.12493. PubMed DOI PMC

Yaqub B.A., Siddique A., Sulimani R. Effects of methylcobalamin on diabetic neuropathy. Clin. Neurol. Neurosurg. 1992;94:105–111. doi: 10.1016/0303-8467(92)90066-C. PubMed DOI

Wang X., Yang W., Zhu Y., Zhang S., Jiang M., Hu J., Zhang H.-H. Genomic DNA methylation in diabetic chronic complications in patients with type 2 diabetes mellitus. Front. Endocrinol. 2022;13:896511. doi: 10.3389/fendo.2022.896511. PubMed DOI PMC

Guo K., Elzinga S., Eid S., Figueroa-Romero C., Hinder L.M., Pacut C., Feldman E.L., Hur J. Genome-wide DNA methylation profiling of human diabetic peripheral neuropathy in subjects with type 2 diabetes mellitus. Epigenetics. 2019;14:766–779. doi: 10.1080/15592294.2019.1615352. PubMed DOI PMC

Guo K., Eid S.A., Elzinga S.E., Pacut C., Feldman E.L., Hur J. Genome-wide profiling of DNA methylation and gene expression identifies candidate genes for human diabetic neuropathy. Clin. Epigenet. 2020;12:123. doi: 10.1186/s13148-020-00913-6. PubMed DOI PMC

Haslbeck K., Schleicher E., Friess U., Kirchner A., Neundörfer B., Heuss D. N ε-carboxymethyllysine in diabetic and non-diabetic polyneuropathies. Acta Neuropathol. 2002;104:45–52. doi: 10.1007/s00401-002-0518-8. PubMed DOI

Luciani A., Schumann A., Berquez M., Chen Z., Nieri D., Failli M., Debaix H., Festa B.P., Tokonami N., Raimondi A., et al. Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency. Nat Commun. 2020;11:970. doi: 10.1038/s41467-020-14729-8. PubMed DOI PMC

Suarez-Moreira E., Yun J., Birch C.S., Williams J.H.H., McCaddon A., Brasch N.E. Vitamin B12 and redox homeostasis: Cob(II)alamin reacts with superoxide at rates approaching superoxide dismutase (SOD) J. Am. Chem. Soc. 2009;131:15078–15079. doi: 10.1021/ja904670x. PubMed DOI

Moreira E.S., Brasch N.E., Yun J. Vitamin B12 protects against superoxide-induced cell injury in human aortic endothelial cells. Free Radic. Biol. Med. 2011;51:876–883. doi: 10.1016/j.freeradbiomed.2011.05.034. PubMed DOI PMC

Chan W., Almasieh M., Catrinescu M.-M., Levin L.A. Cobalamin-associated superoxide scavenging in neuronal cells is a potential mechanism for vitamin B12–Deprivation optic neuropathy. Am. J. Pathol. 2018;188:160–172. doi: 10.1016/j.ajpath.2017.08.032. PubMed DOI PMC

Birch C.S., Brasch N.E., McCaddon A., Williams J.H.H. A novel role for vitamin B12: Cobalamins are intracellular antioxidants in vitro. Free Radic. Biol. Med. 2009;47:184–188. doi: 10.1016/j.freeradbiomed.2009.04.023. PubMed DOI

van de Lagemaat E., de Groot L., van den Heuvel E. Vitamin B12 in relation to oxidative stress: A systematic review. Nutrients. 2019;11:482. doi: 10.3390/nu11020482. PubMed DOI PMC

Mizukami H., Ogasawara S., Yamagishi S.-I., Takahashi K., Yagihashi S. Methylcobalamin effects on diabetic neuropathy and nerve protein kinase C in rats: Methylcobalamin and PKC in diabetic neuropathy. Eur. J. Clin. Investig. 2011;41:442–450. doi: 10.1111/j.1365-2362.2010.02430.x. PubMed DOI

Wolffenbuttel B.H.R., Wouters H.J.C.M., Heiner-Fokkema M.R., van der Klauw M.M. The many faces of cobalamin (vitamin B12) deficiency. Mayo Clin. Proc. Innov. Qual. Outcomes. 2019;3:200–214. doi: 10.1016/j.mayocpiqo.2019.03.002. PubMed DOI PMC

Nexo E., Hoffmann-Lücke E. Holotranscobalamin, a marker of vitamin B-12 status: Analytical aspects and clinical utility. Am. J. Clin. Nutr. 2011;94:359S–365S. doi: 10.3945/ajcn.111.013458. PubMed DOI PMC

Clarke R., Sherliker P., Hin H., Nexo E., Hvas A.M., Schneede J., Birks J., Ueland P.M., Emmens K., Scott J.M., et al. Detection of vitamin B12 deficiency in older people by measuring vitamin B12 or the active fraction of vitamin B12, holotranscobalamin. Clin. Chem. 2007;53:963–970. doi: 10.1373/clinchem.2006.080382. PubMed DOI

Gwathmey K.G., Grogan J. Nutritional neuropathies. Muscle Nerve. 2020;62:13–29. doi: 10.1002/mus.26783. PubMed DOI

Herrmann W., Obeid R., Schorr H., Geisel J. Functional vitamin B12 deficiency and determination of holotranscobalamin in populations at risk. Clin. Chem. Lab. Med. 2003;41:1478–1488. doi: 10.1515/CCLM.2003.227. PubMed DOI

Golding P.H. Holotranscobalamin (HoloTC, Active-B12) and herbert’s model for the development of vitamin B12 deficiency: A review and alternative hypothesis. SpringerPlus. 2016;5:668. doi: 10.1186/s40064-016-2252-z. PubMed DOI PMC

Risch M., Meier D.W., Sakem B., Escobar P.M., Risch C., Nydegger U., Risch L. Vitamin B12 and folate levels in healthy swiss senior citizens: A prospective study evaluating reference intervals and decision limits. BMC Geriatr. 2015;15:82. doi: 10.1186/s12877-015-0060-x. PubMed DOI PMC

Aparicio-Ugarriza R., Palacios G., Alder M., González-Gross M. A review of the cut-off points for the diagnosis of vitamin B12 deficiency in the general population. Clin. Chem. Lab. Med. CCLM. 2015;53:1149–1159. doi: 10.1515/cclm-2014-0784. PubMed DOI

Hannibal L., Lysne V., Bjørke-Monsen A.-L., Behringer S., Grünert S.C., Spiekerkoetter U., Jacobsen D.W., Blom H.J. Biomarkers and algorithms for the diagnosis of vitamin B12 deficiency. Front. Mol. Biosci. 2016;3:27. doi: 10.3389/fmolb.2016.00027. PubMed DOI PMC

Herrmann W., Obeid R. Causes and early diagnosis of vitamin B12 deficiency. Dtsch. Ärzteblatt Int. 2008;105:680–685. doi: 10.3238/arztebl.2008.0680. PubMed DOI PMC

Abildgaard A., Knudsen C.S., Hoejskov C.S., Greibe E., Parkner T. Reference intervals for plasma vitamin B12 and plasma/serum methylmalonic acid in Danish children, adults and elderly. Clin. Chim. Acta. 2022;525:62–68. doi: 10.1016/j.cca.2021.12.015. PubMed DOI

Department of Medicine and Geriatrics, Caritas Medical Centre, Shamshuipo, Hong Kong. Wong C. Vitamin B12 deficiency in the elderly: Is it worth screening? Hong Kong Med. J. 2015;21:155–164. doi: 10.12809/hkmj144383. PubMed DOI

Porter K.M., Hoey L., Hughes C.F., Ward M., Clements M., Strain J., Cunningham C., Casey M.C., Tracey F., O’Kane M., et al. Associations of atrophic gastritis and proton-pump inhibitor drug use with vitamin B-12 status, and the impact of fortified foods, in older adults. Am. J. Clin. Nutr. 2021;114:1286–1294. doi: 10.1093/ajcn/nqab193. PubMed DOI PMC

Nardin R.A., Amick A.N.H., Raynor E.M. Vitamin B12 and methylmalonic acid levels in patients presenting with polyneuropathy. Muscle Nerve. 2007;36:532–535. doi: 10.1002/mus.20845. PubMed DOI