The epidemiology and importance of vitamin B12 screening in diabetic patients

Abrar A. A. Yamani, Jameel A. Awadain, Yousif A. A. Saleh, Mohammad S. Baothman, Feras H. Alhussainy, Mazen S. Alshehri, Helal J. Alharthi, Abdulmalek R. Alqwizani, Abdulrahman A. Alrehaili, Ruwaidah H. Melebary, Manar H. Alanazi


Peripheral neuropathy is a commonly reported chronic adverse event among diabetes mellitus (DM) patients secondary to poor glycemic control. It might also result secondary to deficiency of vitamin B12, reportedly common among diabetic patients. Deficiency of vitamin B12 might result from prolonged metformin administration in patients with type II DM (T2DM). It might also result from reduced absorption and impaired metabolism-related events in type I DM (T1DM) patients. This occurs secondary to the presence of associated autoimmune disorders. Vitamin B12 deficiency is a commonly encountered condition among diabetic patients, both T1DM and T2DM, with variable etiologies. Our current study discussed the epidemiology and importance of screening of vitamin B12 in these patients. However, our findings show that screening is not commonly practiced in different settings. Therefore, awareness is low about the benefits and complications of this practice. Therefore, further research is encouraged to alleviate the quality of care in diabetic patients. Screening for vitamin B12 deficiency might intervene against any potential complications, including irreversible, painful, and potentially disabling nerve injury. Accordingly, it is recommended that screening should be initiated since the start of metformin administration and every year or when relevant clinical manifestations were reported.


Anemia, Vitamin B12 deficiency, Diabetes mellitus, Epidemiology, Management, Screening

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Mekala KC, Bertoni AG. Epidemiology of diabetes mellitus. In: Transplantation, bioengineering, and regeneration of the endocrine pancreas. Elsevier. 2020:49-58.

Reusch JE, Manson JE. Management of Type 2 Diabetes in 2017: Getting to Goal. JAMA. 2017;317(10):1015-6.

Imam K. Management and treatment of diabetes mellitus. Adv Exp Med Biol. 2012;771:356-80.

Bailes BK. Diabetes mellitus and its chronic complications. AORN J. 2002;76(2):266-76.

Papatheodorou K, Banach M, Bekiari E, Rizzo M, Edmonds M. Complications of Diabetes 2017. J Diabetes Res. 2018;2018:3086167.

Oh R, Brown DL. Vitamin B12 deficiency. Am Fam Phys. 2003;67(5):979-86.

Fogelman Y, Kitai E, Blumberg G, Golan-Cohen A, Rapoport M, Carmeli E. Vitamin B12 screening in metformin-treated diabetics in primary care: were elderly patients less likely to be tested? Aging Clin Exp Res. 2017;29.

Albai O, Timar B, Paun DL, Sima A, Roman D, Timar R. Metformin Treatment: A Potential Cause of Megaloblastic Anemia in Patients with Type 2 Diabetes Mellitus. Diabetes, metabolic syndrome and obesity : targets and therapy. 2020;13:3873-8.

Owhin SO, Adaja TM, Fasipe OJ, Akhideno PE, Kalejaiye OO, Kehinde MO. Prevalence of vitamin B(12) deficiency among metformin-treated type 2 diabetic patients in a tertiary institution, South-South Nigeria. SAGE Open Med. 2019;7:2050312119853433.

Kumthekar AA, Gidwani HV, Kumthekar AB. Metformin associated B12 deficiency. J Assoc Phys India. 2012;60:58-60.

Liu KW, Dai LK, Jean W. Metformin-related vitamin B12 deficiency. Age and ageing. 2006;35(2):200-1.

Nervo M, Lubini A, Raimundo FV. Vitamin B12 in metformin-treated diabetic patients: a cross-sectional study in Brazil. Revista da Associacao Medica Brasileira (1992). 2011;57(1):46-9.

Pflipsen MC, Oh RC, Saguil A, Seehusen DA, Seaquist D, Topolski R. The prevalence of vitamin B(12) deficiency in patients with type 2 diabetes: a cross-sectional study. J Am Board Fam Med. 2009;22(5):528-34.

Qureshi SA, Ainsworth A, Winocour PH. Metformin therapy and assessment for vitamin B12 deficiency: is it necessary? Practical Diabetes. 2011;28(7):302-4.

Reinstatler L, Qi YP, Williamson RS, Garn JV, Oakley GP. 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):327-33.

Kos E, Liszek MJ, Emanuele MA, Durazo-Arvizu R, Camacho P. Effect of metformin therapy on vitamin D and vitamin B₁₂ levels in patients with type 2 diabetes mellitus. Endocrine Practice. 2012;18(2):179-84.

Loikas S, Koskinen P, Irjala K. Vitamin B12 deficiency in the aged: a population-based study. Age and ageing. 2007;36(2):177-83.

Yajnik CS, Deshpande SS, Lubree HG, et al. Vitamin B12 deficiency and hyperhomocysteinemia in rural and urban Indians. The Journal of the Association of Physicians of India. 2006;54:775-782.

Shobha V, Tarey SD, Singh RG. Vitamin B₁₂ deficiency & levels of metabolites in an apparently normal urban south Indian elderly population. Indian J Med Res. 2011;134(4):432-9.

Standards of medical care in diabetes--2012. Diabetes Care. 2012;35(1):11-63.

Day C. ADA-EASD diabetes guidance: individualised treatment of hyperglycaemia. Br J Diabetes Vascular Dis. 2012;12(3):146-51.

DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med. 1995;333(9):541-9.

de Jager J, Kooy A, Lehert P. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ. 2010;340:2181.

Ting RZ, Szeto CC, Chan MH, Ma KK, Chow KM. Risk factors of vitamin B(12) deficiency in patients receiving metformin. Arch Int Med. 2006;166(18):1975-9.

Son PT, Reda A, Viet DC. Exchange transfusion in the management of critical pertussis in young infants: a case series. Vox Sang. 2021;116(9):976-82.

Dibas M, Doheim MF, Ghozy S, Ros MH, El-Helw GO, Reda A. Incidence and survival rates and trends of skull Base chondrosarcoma: A Population-Based study. Clin Neurol Neurosurg. 2020;198:106153.

Wulffelé MG, Kooy A, Lehert P, et al. 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. Journal of internal medicine. 2003;254(5):455-463.

Andrès E, Noel E, Goichot B. Metformin-associated vitamin B12 deficiency. Arch Int Med. 2002;162(19):2251-2.

Bauman WA, Shaw S, Jayatilleke E, Spungen AM, Herbert V. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care. 2000;23(9):1227-31.

Nguyen TM, Huan VT, Reda A. Clinical features and outcomes of neonatal dengue at the Children's Hospital 1, Ho Chi Minh, Vietnam. J Clin Virol. 2021;138:104758.

De Block CE, De Leeuw IH, Van Gaal LF. Autoimmune gastritis in type 1 diabetes: a clinically oriented review. J Clin Endocrinol Metab. 2008;93(2):363-71.

Van den Driessche A, Eenkhoorn V, Van Gaal L, De Block C. Type 1 diabetes and autoimmune polyglandular syndrome: a clinical review. Netherlands J Med. 2009;67(11):376-87.

Koshy AS, Kumari SJ, Ayyar V, Kumar P. Evaluation of serum vitamin B12 levels in type 1 diabetics attending a tertiary care hospital: A preliminary cross - sectional study. Indian J Endocrinol Metab. 2012;16(1):79-82.

De Block CE, De Leeuw IH, Rooman RP, Winnock F, Du Caju MV, Van Gaal LF. Gastric parietal cell antibodies are associated with glutamic acid decarboxylase-65 antibodies and the HLA DQA1*0501-DQB1*0301 haplotype in Type 1 diabetes mellitus. Belgian Diabetes Registry. Diabetic Med. 2000;17(8):618-22.

De Block CE, De Leeuw IH, Van Gaal LF. High prevalence of manifestations of gastric autoimmunity in parietal cell antibody-positive type 1 (insulin-dependent) diabetic patients. The Belgian Diabetes Registry. J Clin Endocrinol Metab. 1999;84(11):4062-7.

Riley WJ, Toskes PP, Maclaren NK, Silverstein JH. Predictive value of gastric parietal cell autoantibodies as a marker for gastric and hematologic abnormalities associated with insulin-dependent diabetes. Diabetes. 1982;31(12):1051-5.

Fein HG, Rivlin RS. Anemia in thyroid diseases. Med Clin North Am. 1975;59(5):1133-45.

Rewers M, Liu E, Simmons J, Redondo MJ, Hoffenberg EJ. Celiac disease associated with type 1 diabetes mellitus. Endocrinol Metab Clin North Am. 2004;33(1):197-214.

Roberts CG, Ladenson PW. Hypothyroidism. Lancet (London, England). 2004;363(9411):793-803.

Barker JM. Clinical review: Type 1 diabetes-associated autoimmunity: natural history, genetic associations, and screening. J Clin Endocrinol Metab. 2006;91(4):1210-7.

Joffe B, Distiller L, Landau S, Blacking L, Klisiewicz A. Spectrum o f Autoimmune Disorders in Type 1 Diabetes–A Cross-Sectional Clinical Audit. J Diabetes Metab. 2010;1(112):2.

Selimoğlu MA, Karabiber H. Celiac disease: prevention and treatment. J Clin Gastroenterol. 2010;44(1):4-8.

Kim J, Ahn CW, Fang S, Lee HS, Park JS. Association between metformin dose and vitamin B12 deficiency in patients with type 2 diabetes. Medicine (Baltimore). 2019;98(46):e17918.

Ko SH, Ko SH, Ahn YB. Association of vitamin B12 deficiency and metformin use in patients with type 2 diabetes. J Korean Med Sci. 2014;29(7):965-72.

Sato Y, Ouchi K, Funase Y, Yamauchi K, Aizawa T. Relationship between metformin use, vitamin B12 deficiency, hyperhomocysteinemia and vascular complications in patients with type 2 diabetes. Endocrine J. 2013;60(12):1275-80.

Alshammari AN, Iqbal R, Baksh IP. Vitamin B12 deficiency and the knowledge and practice of physicians regarding screening for vitamin B12 deficiency among type 2 diabetic patients on metformin in selected hospitals in Riyadh, Saudi Arabia. J Family Med Prim Care. 2019;8(7):2306-11.

Mazokopakis EE, Starakis IK. Recommendations for diagnosis and management of metformin-induced vitamin B12 (Cbl) deficiency. Diabetes Res Clin Pract. 2012;97(3):359-67.

Snow CF. Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician. Arch Int Med. 1999;159(12):1289-98.

Klee GG. Cobalamin and folate evaluation: measurement of methylmalonic acid and homocysteine vs vitamin B(12) and folate. Clin Chem. 2000;46(8):1277-83.