Vitamin B12 Deficiency



Diabetes and its sequelae 


Diabetes is a life-long condition that results from the inability of the body to control levels of glucose in the blood. As a result, blood glucose levels rise uncontrollably. Many of the complications of diabetes arise from the inability to successfully maintain normal glucose levels. Apart from the obvious problem of glucose control, other complications of diabetes can be  the development of neuritis, which is an inflammation of a nerve or nerves. This inflammation usually manifests itself in pain in the area of affliction. It also may result in paresthesia (pins and needles), paresia (weakness), hypoesthesia (numbness), paralysis, wasting and disappearance of reflexes. In diseases such as Diabetes, one or many nerves can be affected. If neuritis is left untreated it can lead to permanent nerve damage and debilitation. The continued high level of glucose can also lead to complication such as heart disease and blindness. Type II diabetes has recently been linked to inflammation in fat cells.


Vitamin B12 Deficiency, Metformin Use and Diabetes 


Vitamin B12 helps to maintain healthy nerve cells and blood cells. Several studies have have shown that vitamin B12 deficiency can lead to several conditions in diabetic persons. The use of Metformin (brand names Glucophage, Glucophage XR, Fortamet, Riomet, Glumetza, and others) early in the treatment of type II diabetes leads to a steady reduction in serum vitamin B12 ultimately leading to symptoms of vitamin B12 deficiency. The extent of vitamin B12 reduction is dependent upon the dose and length of time that the person uses the drug. The development of sub-clinical deficiency also depends very much on the starting level of vitamin B12 in the diabetic person. The subsequent deficiency in vitamin B12 can in turn lead to an increase in serum homocysteine levels. Increases in the level of homocysteine has been shown to correlate with increases in cardiovascular disease, diabetic neuritis and it has now been shown that it is an independent risk factor  for the development of diabetic retinopathy.   Patients who have been on Metformin medication for some time often exhibit many of the symptoms of vitamin B12 deficiency, including paleness, shortness of breath, fatigue, weakness, numbness and tingling of hands and feet, and signs of cognitive impairment, such as short term memory loss. and reduced cognitive function (1-41). Administration of vitamin B12 can reduce serum levels of serum homocysteine, which will in turn reduce pain, initiate repair to the myelin sheaths, and promote regeneration of the nerve cells in conditions such as diabetic neuropathy and diabetic retinopathy. Vitamin B12 supplementation to treat vitamin B12 deficiency can also reduce the levels of methyl malonic acid (MMA) in serum. MMA is a by-product of insufficient utilization of fatty acids and amino acids for energy production. Thus, supplementation with Adenosylcobalamin (a particular form of the vitamin) can help to regain energy stores in diabetic patients who are taking metformin, who often have continued feelings of exhaustion. High doses of vitamin B12 have been shown reduce the inflammatory response seen in many conditions, such as neuritis and as such may be of benefit to persons with diabetes. .


Treatment of vitamin B12 deficiency in the Diabetic Patient 


Once a person is showing signs of vitamin B12 deficiency it is almost impossible to provide enough vitamin B12 with oral supplements to restore both the serum levels of vitamin B12 and the levels in the central spinal fluid and the brain. It has recently become apparent that oral supplementation with vitamin B12 does not provide enough vitamin B12 to overcome vitamin B12 deficiency due to the limited uptake capacity of the intestine for vitamin B12, hence there is a requirement for higher initial doses of vitamin B12 to be supplied either by injection or via the topical vitamin B12 formulation.  Recently a topical form of vitamin B12 has been developed that is a specially formulated preparation that is an easy to apply, needle-free delivery system suitable for application to the skin of the Diabetes patient. This pain-free form of delivery greatly increases the patient comfort experienced during the administration of the medication and allows for self-medication without the need for medical staff or any special training. In addition, the topical formulation is particularly suited to diabetes patients who are on Metformin™ medication, as these patients continue to have poor absorption of the vitamin from the intestine. Such patients generally cannot absorb adequate amounts of vitamin B12 from oral supplements.. 


Further Information on Neuritis, Peripheral Neuropathy and Vitamin B12 Deficiency, Metformin use and diabetes

Check out the following sites for further information:

  1. Porter et al. Hyperglycemia and metformin use are associated with B-vitamin deficiency and cognitive dysfunction in older adults.

  2. Mazokopakis and Starakis Recommendations for diagnosis and management of metformin-induced vitamin B12 (Cbl) deficiency. Diabetes Res Clin Pract. 2012: 359-67

  3. Gatford et al Vitamin B12 and homocysteine status during pregnancy in the metformin in gestational diabetes trial.... Diabetes Obes. Metab.2013

  4. Mahajan and Gupta Revisiting metformin: annual vitamin B12 supplementation can become mandatory with long-term metformin use. J Young Pharm. 2010: 428-9

  5. Greibe E, Miller JW, Foutouhi SH, Green R, Nexo E. Metformin increases liver accumulation of vitamin B12 - An experimental study in rats. Biochimie. 2013 Feb 10. doi:pii: S0300-9084(13)00043-6. 10.1016/j.biochi.2013.02.002.

  6. Ouvarovskaia V, Portillo K, Delgado MT, Requeno MN, Torrente JI, Pinilla M, Aranda C, Perez MP. [Vitamin B(12) deficiency in type 2 diabetics treated with metformin]. Aten Primaria. 2013 Feb;45(2):121-2. doi: 10.1016/j.aprim.2012.08.003. Epub 2012 Dec 13. 

  7. Long AN, Atwell CL, Yoo W, Solomon SS. Vitamin B(12) deficiency associated with concomitant metformin and proton pump inhibitor use. Diabetes Care. 2012 Dec;35(12):e84. doi: 10.2337/dc12-0980.

  8. Pierce SA, Chung AH, Black KK. Evaluation of vitamin B12 monitoring in a veteran population on long-term, high-dose metformin therapy. Ann Pharmacother. 2012 Nov;46(11):1470-6. doi: 10.1345/aph.1R223. Epub 2012 Oct 31.

  9. Calvo Romero JM, Ramiro Lozano JM. Vitamin B(12) in type 2 diabetic patients treated with metformin. Endocrinol Nutr. 2012 Oct;59(8):487-90. doi: 10.1016/j.endonu.2012.06.005. Epub 2012

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

  11. Mazokopakis EE, Starakis IK. Recommendations for diagnosis and management of metformin-induced vitamin B12 (Cbl) deficiency. Diabetes Res Clin Pract. 2012 Jul 7.

  12. Moore E, Mander A, Ames D, Carne R, Sanders K, Watters D. Cognitive impairment and vitamin B12: a review. Int Psychogeriatr. 2012 Jan 6:1-16.

  13. 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 Feb;35(2):327-33. Epub 2011 Dec 16.

  14. 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. Endocr Pract. 2012 Mar-Apr;18(2):179-84.

  15. Moore E, Mander A, Watters D. More adverse neurological consequences of metformin-induced vitamin B12 deficiency. South Med J. 2011 Jul;104(7):541-2;

  16. Sando KR, Barboza J, Willis C, Taylor J. Recent diabetes issues affecting the primary care clinician. South Med J. 2011 Jun;104(6):456-61. Review.

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  19. Mahajan R, Gupta K. Revisiting Metformin: Annual Vitamin B12 Supplementation may become Mandatory with Long-Term Metformin Use. J Young Pharm. 2010 Oct;2(4):428-9.

  20. Bundrick JB, Litin SC. Clinical pearls in general internal medicine. Mayo Clin Proc. 2011 Jan;86(1):70-4.

  21. Diabetes drug interferes with vitamin B12. Harv Heart Lett. 2010 May;20(9):7.

  22. Vidal-Alaball J, Butler CC. Reduced serum vitamin B-12 in patients taking metformin. BMJ. 2010 May 20;340:c2198. doi: 10.1136/bmj.c2198.

  23. de Jager J, Kooy A, Lehert P, Wulffelé MG, van der Kolk J, Bets D, Verburg J, Donker AJ, Stehouwer CD. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ. 2010 May 20;340:c2181. doi: 10.1136/bmj.c2181.

  24. Berlie HD, Garwood CL. Diabetes medications related to an increased risk of falls and fall-related morbidity in the elderly. Ann Pharmacother. 2010 Apr;44(4):712-7.

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  26. Bell DS. Metformin-induced vitamin B12 deficiency presenting as a peripheral neuropathy. South Med J. 2010 Mar;103(3):265-7.

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  30. Andrès E, Noel E, Goichot B. Metformin-associated vitamin B12 deficiency. Arch Intern Med. 2002 Oct 28;162(19):2251-2.

  31. Gilligan MA. Metformin and vitamin B12 deficiency. Arch Intern Med. 2002 Feb 25;162(4):484-5

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  34. Fujita H, Narita T, Yoshioka N, Hosoba M, Ito S. A case of megaloblastic anemia due to vitamin B12 deficiency precipitated in a totally gastrectomized type II diabetic patient following the introduction of metformin therapy. Endocr J. 2003 Aug;50(4):483-4.

  35. Andrès E, Perrin AE, Demangeat C, Kurtz JE, Vinzio S, Grunenberger F, Goichot B, Schlienger JL. The syndrome of food-cobalamin malabsorption revisited in a department of internal medicine. A monocentric cohort study of 80 patients. Eur J Intern Med. 2003 Jul;14(4):221-226.

  36. Andrès E, Noel E, Goichot B. Metformin-associated vitamin B12 deficiency. Arch Intern Med. 2002 Oct 28;162(19):2251-2.

  37. Gilligan MA. Metformin and vitamin B12 deficiency. Arch Intern Med. 2002 Feb 25;162(4):484-5.

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  39. Berger W. Incidence of severe side-effects during therapy with sulfonylureas and biguanides. Horm Metab Res Suppl. 1985;15:111-5.

  40. Adams JF, Clark JS, Ireland JT, Kesson CM, Watson WS. Malabsorption of vitamin B12 and intrinsic factor secretion during biguanide therapy. Diabetologia. 1983 Jan;24(1):16-8

  41. Caspary WF, Zavada I, Reimold W, Deuticke U, Emrich D, Willms B. Alteration of bile acid metabolism and vitamin-B12-absorption in diabetics on biguanides. Diabetologia. 1977 May;13(3):187-93

Scientific publications on vitamin B12 and neuritis can be found at the following link



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The statements on this site compose a compendium of generally recognized signs of vitamin B12 deficiency, and problems that can then ensue They also are formulated from a summary of relevant scientific publications. In addition they may contain some forward looking statements of a general nature.
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