Vitamin B12 Levels in Type 2 Diabetes Patients on Metformin in Gaza Strip-Palestine

October 2, 2018


Background: Metformin is the most common oral hypoglycemic agent that used to treat Type 2 Diabetes Mellitus(T2DM) patients, which associated side effects such as Vitamin B12(VB12) deficiency.

Objective: This study was carried out to determine the serum level of vitamin B12 in Palestinian patients with T2DM  lived in Gaza Strip.

Materials And Methods: We conducted cross sectional study comprised 73T2DM patients on Metformin. Questionnaire interview was applied. Blood samples were collected  for CBC and  VB12 detection. VB12 deficiency was defined as serum concentration of <300 pg/ml.

Results: There was significantly lower  in mean of  vitamin B12 level in participants who have used metformin for ≥5years and in patients who were on metformin at a dose of 1000 mg/ day. Duration of metformin use were associated with increased risk of B12 deficiency 4.9 times (OR= 4.9) which increases the risk of DM complications 2.7 times . The results showed that 100 mg increase in metformin dose was associated with a 19.3 ± 4.4 pg/ ml (P = 0.00) lowering Vitamin B12 level. Every one year increase in the duration of diabetes associated with18.6 ± 6.7 pg/ ml( P =0.007) lowering in VB12 level.

Conclusion : Low serum VB12 level is associated with longer duration and higher dose of metformin use. Therefore, routine determination of VB12 level in patients with T2DM on high dose of metformin and those with prolonged use of metformin might help in identifying patients that would benefit from VB12 supplements.


Type-2 Diabetes Mellitus , Metformin, Vitamin B12 Deficiency


Koppad, A. K., Patil, G., Baligar, B. D., & Renukappa, V. B.(2017) Evaluation of serum vitamin B12 levels in type 2 diabetics patients on metformin therapy attending a tertiary care hospital. Journal of Evidence Based Medicine and Healthcare, 4(90), 5399-5404

Luo, Y., Zhang, X., Li, Y., Deng, J., Li, X., Qu, Y., ... & Lin, B. (2018). High-glucose 3D INS-1 cell model combined with a microfluidic circular concentration gradient generator for high throughput screening of drugs against type 2 diabetes. RSC Advances, 8(45), 25409-25416.‏

Maruthur, NM; Tseng, E; Hutfless, S; Wilson, LM; Suarez-Cuervo, C; Berger, Z; Chu, Y; Iyoha, E; Segal, JB; Bolen, S (19 April 2016). "Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis". Annals of Internal Medicine. 164 (11): 740–5

Toh SY, Zarshenas N, Jorgensen J. Prevalence of nutrient deficiencies in bariatric patients. Nutrition. 2009; 25:1150. PubMed

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

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): 1227-1231.

Sigel, A., Sigel, H., & Sigel, R. K. (Eds.). (2013). Interrelations between essential metal ions and human diseases. Springer Netherlands.

Green R. Physiology, dietary sources, and requirements. In: Encyclopedia of human nutrition . Vol 4. Academic Press, 2013: 351-6.‏

Miller A, Korem M, Almog R, Galboiz Y (June 2005). "Vitamin B12, demyelination, remyelination and repair in multiple sclerosis". Journal of the Neurological Sciences. 233 (1–2): 93–7.

Greer JP (2014). Wintrobe's Clinical Hematology Thirteenth Edition. Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins. ISBN 978-1-4511-7268-3.

Stabler S. Vitamin B12 deficiency. N Engl J Med 2013;368:149-60.

Gorska R ,Sobczyńska-Malefora A, Pelisser M, Ruwona P, Witchlow B, Harrington D. An audit of holotranscobalamin (“Active” B12) and methylmalonic acid assays for the assessment of vitamin B12 status: application in a mixed patient population. Clin Biochem 2014;47:82-6.

Trijbels FJ, van der Put NM, van Straaten HW, Blom HJ (April 2001). "Folate, homocysteine and neural tube defects: an overview". Experimental Biology and Medicine. 226 (4): 243–70.

Kooy A, Wulffele M, 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. J Intern Med. 2003; 254:455–63.

Andres, E., Loukili, N. H., Noel, E., Kaltenbach, G., Abdelgheni, M. B., Perrin, A. E. & Blicklé, J. F. (2004). Vitamin B12 (cobalamin) deficiency in elderly patients.

Khan, A., Shafiq, I., & Shah, M. H. (2017). Prevalence of Vitamin B12 Deficiency in Patients with Type II Diabetes Mellitus on Metformin: A Study from Khyber Pakhtunkhwa. Cureus, 9(8).‏

Reinstatler L, Qi YP, Williamson RS, Garn JV, Oakley GP Jr. Association of biochemical B12 deficiency with metformin therapy and Vitamin B12 supplements: The National Health and Nutrition Examination Survey, 1999-2006. Diabetes Care 2012;35:327-33.

Calvo Romero JM, Ramiro Lozano JM. Vitamin B(12) in type 2 diabetic patients treated with metformin. Endocrinol Nutr 2012;59:487-90.

Nervo, M., Lubini, A., Raimundo, F. V., Faulhaber, G. A. M., Leite, C., Fischer, L. M., & Furlanetto, T. W. (2011). Vitamin B12 in metformin-treated diabetic patients: a cross-sectional study in Brazil. Rev Assoc Med Bras ;57(1), 46-49.

Ting RZ, Szeto CC, Chan MH, Ma KK, Chow KM. Risk factors of vitamin B12 deficiency in patients receiving metformin. Arch Internal Med. 2006; 166(18):1975-9.PubMed .

Filioussi K, Bonvoas S, Katsaros T. Should we screen diabetes patients using biguanides for megaloblastic anaemia. Aust Fam Physician. 2003; 32(5): 383-4.PubMed

Iftikhar R.,&, kamran S., Qadir A., Iqbal Z., Bin usman H.. Prevalence of Vitamin B12 deficiency in patients of type 2 diabetes mellitus on metformin: A case control study from Pakistan. Pan African Medical Journal. 2013,1937- 8688.

Florence G., Giacomo G., Thibaud M., Ariane S., Christophe P., Jean-Paul C., Valérie M., Denis MG., Eric R., Anne-Marie D., Antoine A. (2017) Clinical Consequences of Metformin-Associated Vitamin B12 Deficiency Among Patients with Type 2 Diabetes. JSM Nutritional Disorders 1(1): 1002.

Rana, R., Fayyaz, M., Iftikhar, T., Ullah Makki M. (2017). Metformin use and Vitamin B12 deficiency in patients with Type 2 Diabetes Mellitus. James Madison High School, 11(3) 1017-1020.

Khan, A., Shafiq, I., & Shah, M. H. (2017). Prevalence of Vitamin B12 Deficiency in Patients with Type II Diabetes Mellitus on Metformin: A Study from Khyber Pakhtunkhwa. Cureus, 9(8).‏

Verma V., Nim R., Singh P., Kumar M., Singh G., Singh AK. Vitamin B12 deficiency among vegetarian and non-vegetarian diabetic population receiving prolonged Metformin based oral hypoglycemic agents therapy International Journal of Advances in Medicine;4(4):1150-1154.

de Groot Kamphuis DM, van Dijk PR, Groenier KH, Houweling ST, Bilo HJ, Kleefstra N. Vitamin B12 deficiency and the lack of its consequences in type 2 diabetes patients using metformin. Neth J Med 2013;71:386 90.

Oberley MJ, Yang DT (2013). Laboratory testing for cobalamin deficiency in megaloblastic anemia. American Journal of Hematology;88:522-526.

Zalaket, J., Wehbe, T., & Jaoude, E. A. (2018). Vitamin B12 deficiency in diabetic subjects taking metformin: A cross sectional study in a Lebanese cohort. Journal of Nutrition & Intermediary Metabolism; 11(4), 9-13.‏

Shailendra D., Kalani, R., Narayan, K. V., Prabhakaran, D., Tandon, N., & Reddy, P. S. (2018). Prevalence of vitamin B12 deficiency among individuals with type 2 diabetes mellitus in a South Indian rural community. International Journal of Basic & Clinical Pharmacology; 7(2), 309-314.‏

Ko S-H, Ahn Y-B, Song K-H, Han K-D, Park Y-M, Kim H-S (2014). Association of Vitamin B12 Deficiency and Metformin Use in Patients with Type 2 Diabetes. Journal Korean Medical Science; 29:965–972.

Akinlade, K. S., Agbebaku, S. O., Rahamon, S. K., & Balogun, W. O. (2015). Vitamin B 12 levels in patients with type 2 diabetes mellitus on metformin. Annals of Ibadan postgraduate medicine, 13(2), 79-83.‏

Author Details

Lamia'a S. Saqer

Mohammed I. Al-majaidah

Youssef O. Safi

Salem S. Shbair Shbair

Tareq Z. Abu-Azab