open access

Vol 9, No 6 (2020)
Review paper
Published online: 2020-11-26
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Vitamin B12 in diabetes — a new treatment paradigm?

Beata Mrozikiewicz-Rakowska, Agata Chylińska, Damian Sieńko, Leszek Czupryniak
DOI: 10.5603/DK.2020.0060
Clinical Diabetology 2020;9(6):497-504.

open access

Vol 9, No 6 (2020)
Published online: 2020-11-26


Vitamin B12 supplementation in specific clinical conditions in diabetic patients has been recommended in the guidelines. These recommendations reflect reports confirming the importance of vitamin B12 supplementation in the treatment of diabetic complications, as well as to correct its deficiency during metformin treatment. In the present article, we reviewed the issue of vitamin B12 deficiency, the relevant diagnostic approach, and the rationale for vitamin B12 supplementation in diabetic patients.


Vitamin B12 supplementation in specific clinical conditions in diabetic patients has been recommended in the guidelines. These recommendations reflect reports confirming the importance of vitamin B12 supplementation in the treatment of diabetic complications, as well as to correct its deficiency during metformin treatment. In the present article, we reviewed the issue of vitamin B12 deficiency, the relevant diagnostic approach, and the rationale for vitamin B12 supplementation in diabetic patients.

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vitamin B12; diabetes; metformin; diabetic neuropathy

About this article

Vitamin B12 in diabetes — a new treatment paradigm?


Clinical Diabetology


Vol 9, No 6 (2020)

Article type

Review paper



Published online




Bibliographic record

Clinical Diabetology 2020;9(6):497-504.


vitamin B12
diabetic neuropathy


Beata Mrozikiewicz-Rakowska
Agata Chylińska
Damian Sieńko
Leszek Czupryniak

References (57)
  1. Paoloni-Giacobino A, Grimble R, Pichard C. Genetics and nutrition. Clinical Nutrition. 2003; 22(5): 429–435.
  2. Kośmider A. Czaczyk, K. Witamina B12 - budowa, biosynteza, funkcje i metody oznaczania. Żywność Nauka Technologia Jakość. 2010; 17(5): 17–32.
  3. Moridani M, Ben-Poorat S. Laboratory Investigation of Vitamin B12Deficiency. Laboratory Medicine. 2006; 37(3): 166–174.
  4. Briani C, Dalla Torre C, Citton V, et al. Cobalamin deficiency: clinical picture and radiological findings. Nutrients. 2013; 5(11): 4521–4539.
  5. Martínez Y, Li X, Liu G, et al. The role of methionine on metabolism, oxidative stress, and diseases. Amino Acids. 2017; 49(12): 2091–2098.
  6. Pawlak R, Lester SE, Babatunde T. The prevalence of cobalamin deficiency among vegetarians assessed by serum vitamin B12: a review of literature. Eur J Clin Nutr. 2016; 70(7): 866.
  7. Battat R, Kopylov U, Byer J, et al. Vitamin B12 deficiency in inflammatory bowel disease: a prospective observational pilot study. Eur J Gastroenterol Hepatol. 2017; 29(12): 1361–1367.
  8. Zheng S, Yang W, Wu C, et al. Association of ulcerative colitis with transcobalamin II gene polymorphisms and serum homocysteine, vitamin B, and folate levels in Chinese patients. Immunogenetics. 2017; 69(7): 421–428.
  9. Sutherland RJ, Cordes DO, Carthew GC. Ovine white liver disease--an hepatic dysfunction associated with vitamin B12 deficiency. N Z Vet J. 1979; 27(11): 227–232.
  10. Glasbrenner B, Malfertheiner P, Büchler M, et al. Vitamin B12 and folic acid deficiency in chronic pancreatitis: a relevant disorder? Klin Wochenschr. 1991; 69(4): 168–172.
  11. Berry N, Basha J, Varma N, et al. Anemia in celiac disease is multifactorial in etiology: A prospective study from India. JGH Open. 2018; 2(5): 196–200.
  12. Adamska A, Nowak M, Piłaciński S, et al. Small intestinal bacterial overgrowth in adult patients with type 1 diabetes: its prevalence and relationship with metabolic control and the presence of chronic complications of the disease. Pol Arch Med Wewn. 2016; 126(9): 628–634.
  13. Majumder S, Soriano J, Louie Cruz A, et al. Vitamin B12 deficiency in patients undergoing bariatric surgery: preventive strategies and key recommendations. Surg Obes Relat Dis. 2013; 9(6): 1013–1019.
  14. Varughese GI, Scarpello JHB. Metformin and vitamin B12 deficiency: the role of H2 receptor antagonists and proton pump inhibitors. Age Ageing. 2007; 36(1): 110–1; discussion 111.
  15. den Elzen WPJ, Groeneveld Y, de Ruijter W, et al. Long-term use of proton pump inhibitors and vitamin B12 status in elderly individuals. Aliment Pharmacol Ther. 2008; 27(6): 491–497.
  16. Linnebank M, Moskau S, Semmler A, et al. Antiepileptic drugs interact with folate and vitamin B12 serum levels. Ann Neurol. 2011; 69(2): 352–359.
  17. Lindenbaum J, Brown AS, Klonowski E, et al. Drugs and vitamin B12 and folate metabolism. Curr Concepts Nutr. 1983; 12: 73–87.
  18. Antonijevic N, Nesovic M, Trbojevic B, et al. Anemia in hypothyroidism. Med Pregl. 1999; 52(3-5): 136–140.
  19. Przybylik-Mazurek E, Kotlinowska B, Kasztelnik M, et al. [Autoimmunological and allergic disorders with Hashimoto and Graves disease]. Przegl Lek. 2006; 63(9): 719–722.
  20. Hagopian W, Lee HS, Liu E, et al. TEDDY Study Group. Co-occurrence of Type 1 Diabetes and Celiac Disease Autoimmunity. Pediatrics. 2017; 140(5).
  21. Shakil A, Church RJ, Rao SS. Gastrointestinal complications of diabetes. Am Fam Physician. 2008; 77(12): 1697–1702.
  22. Krishnamurthy G, Menon A, Kannan K, et al. Coronary artery disease and mesenteric artery stenosis - Two sides of the same coin? - Long term prospective analysis. Intractable Rare Dis Res. 2019; 8(4): 245–251.
  23. Atreja A, Kalra S. Infections in diabetes. J Pak Med Assoc. 2015; 65(9): 1028–1030.
  24. Bauman WA, Shaw S, Jayatilleke E, et al. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care. 2000; 23(9): 1227–1231.
  25. Freeman R. Not all neuropathy in diabetes is of diabetic etiology: differential diagnosis of diabetic neuropathy. Curr Diab Rep. 2009; 9(6): 423–431.
  26. Hansen CS, Jensen JS, Ridderstråle M, et al. Vitamin B12 deficiency is associated with cardiovascular autonomic neuropathy in patients with type 2 diabetes. J Diabetes Complications. 2017; 31(1): 202–208.
  27. Beitzke M, Pfister P, Fortin J, et al. Autonomic dysfunction and hemodynamics in vitamin B12 deficiency. Auton Neurosci. 2002; 97(1): 45–54.
  28. de Greef BTA, Hoeijmakers JGJ, Gorissen-Brouwers CML, et al. Associated conditions in small fiber neuropathy - a large cohort study and review of the literature. Eur J Neurol. 2018; 25(2): 348–355.
  29. Satyanarayana A, Balakrishna N, Pitla S, et al. Status of B-vitamins and homocysteine in diabetic retinopathy: association with vitamin-B12 deficiency and hyperhomocysteinemia. PLoS One. 2011; 6(11): e26747.
  30. Zehetner C, Bechrakis NE. White centered retinal hemorrhages in vitamin b(12) deficiency anemia. Case Rep Ophthalmol. 2011; 2(2): 140–144.
  31. Azenha C, Costa JF, Fonseca P. You are what you eat: ophthalmological manifestations of severe B deficiency. BMJ Case Rep. 2017; 2017.
  32. Chan W, Almasieh M, Catrinescu MM, et al. Cobalamin-Associated Superoxide Scavenging in Neuronal Cells Is a Potential Mechanism for Vitamin B-Deprivation Optic Neuropathy. Am J Pathol. 2018; 188(1): 160–172.
  33. Drzewoski J, Czupryniak L, Chwatko G, et al. Hyperhomocysteinemia in poorly controlled type 2 diabetes patients. Diabetes Nutr Metab. 2000; 13(6): 319–324.
  34. Sreckovic B, Sreckovic VD, Soldatovic I, et al. Homocysteine is a marker for metabolic syndrome and atherosclerosis. Diabetes Metab Syndr. 2017; 11(3): 179–182.
  35. Yigit S, Karakus N, Inanir A. Association of MTHFR gene C677T mutation with diabetic peripheral neuropathy and diabetic retinopathy. Mol Vis. 2013; 19: 1626–1630.
  36. Carlsen SM, Kjøtrød S, Vanky E, et al. Homocysteine levels are unaffected by metformin treatment in both nonpregnant and pregnant women with polycystic ovary syndrome. Acta Obstet Gynecol Scand. 2007; 86(2): 145–150.
  37. Reinstatler L, Qi YP, Williamson RS, et al. Association of biochemical B₁₂ deficiency with metformin therapy and vitamin B₁₂ supplements: the National Health and Nutrition Examination Survey, 1999-2006. Diabetes Care. 2012; 35(2): 327–333.
  38. Ahmed MA. Metformin and Vitamin B12 Deficiency: Where Do We Stand? J Pharm Pharm Sci. 2016; 19(3): 382–398.
  39. Tomkin GH, Hadden DR, Weaver JA, et al. Vitamin-B12 status of patients on long-term metformin therapy. Br Med J. 1971; 2(5763): 685–687.
  40. Sahin M, Tutuncu NB, Ertugrul D, et al. Effects of metformin or rosiglitazone on serum concentrations of homocysteine, folate, and vitamin B12 in patients with type 2 diabetes mellitus. J Diabetes Complications. 2007; 21(2): 118–123.
  41. de Jager J, Kooy A, Lehert P, et al. 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.
  42. Liu Q, Li S, Quan H, et al. Vitamin B12 status in metformin treated patients: systematic review. PLoS One. 2014; 9(6): e100379.
  43. Aroda VR, Edelstein SL, Goldberg RB, et al. Diabetes Prevention Program Research Group. Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab. 2016; 101(4): 1754–1761.
  44. Caspary WF, Creutzfeldt W. Analysis of the inhibitory effect of biguanides on glucose absorption: inhibition of active sugar transport. Diabetologia. 1971; 7(5): 379–385.
  45. Buvat DR. Use of metformin is a cause of vitamin B12 deficiency. Am Fam Physician. 2004; 69(2): 264; author reply 264, 266.
  46. Gupta K, Jain A, Rohatgi A. An observational study of vitamin b12 levels and peripheral neuropathy profile in patients of diabetes mellitus on metformin therapy. Diabetes Metab Syndr. 2018; 12(1): 51–58.
  47. Wile DJ, Toth C. Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy. Diabetes Care. 2010; 33(1): 156–161.
  48. Singh AK, Kumar A, Karmakar D, et al. Association of B12 deficiency and clinical neuropathy with metformin use in type 2 diabetes patients. J Postgrad Med. 2013; 59(4): 253–257.
  49. Alharbi TJ, Tourkmani AM, Abdelhay O, et al. The association of metformin use with vitamin B12 deficiency and peripheral neuropathy in Saudi individuals with type 2 diabetes mellitus. PLoS One. 2018; 13(10): e0204420.
  50. Ahmed MA, 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(1): 44.
  51. Ahmed MA, Muntingh GL, Rheeder P. Perspectives on Peripheral Neuropathy as a Consequence of Metformin-Induced Vitamin B12 Deficiency in T2DM. Int J Endocrinol. 2017; 2017: 2452853.
  52. Mietlicki-Baase EG, Liberini CG, Workinger JL, et al. A vitamin B12 conjugate of exendin-4 improves glucose tolerance without associated nausea or hypophagia in rodents. Diabetes Obes Metab. 2018; 20(5): 1223–1234.
  53. Association AD. 1. Improving Care and Promoting Health in Populations: Standards of Medical Care in Diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S7-S13. 10.2337/dc20-S001.
  54. Hunt A, Harrington D, Robinson S. Vitamin B12 deficiency. BMJ. 2014; 349: g5226.
  55. Obeid R, Jung J, Falk J, et al. Serum vitamin B12 not reflecting vitamin B12 status in patients with type 2 diabetes. Biochimie. 2013; 95(5): 1056–1061.
  56. Flores-Guerrero JL, Minovic I, Groothof D, et al. Association of Plasma Concentration of Vitamin B12 With All-Cause Mortality in the General Population in the Netherlands. JAMA Netw Open. 2020; 3(1): e1919274.
  57. Bensky MJ, Ayalon-Dangur I, Ayalon-Dangur R, et al. Comparison of sublingual vs. intramuscular administration of vitamin B12 for the treatment of patients with vitamin B12 deficiency. Drug Deliv Transl Res. 2019; 9(3): 625–630.

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