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Metformin is the first-line medication for treatment of type 2 diabetes mellitus (T2DM). This commonly used medication has also been associated with lowering serum vitamin B12 levels. Although the British National Formulary documented this connection in the 1970s with a constellation of studies supporting this effect, recognition of this by most prescribers is lacking.1-17

Three theoretical mechanisms of action regarding the contribution of metformin to the lowering of B12, a water-soluble vitamin, have been postulated; it may be one or any combination of these that contributes to a diminished B12 level. The first posits that this is due to blocking by metformin of the calcium channels in the distal ileum that normally allow absorption of the vitamin B12-intrinsic factor (B12-IF) complex by altering the membrane potential.2 The hydrophobic tail of metformin binds to the hydrocarbon core of the cell membrane, imparting a net positive charge; this, in turn, repels calcium that is necessary for transporting B12 across the ileal-lumen interface.18 The second mechanism details the modification of normal bacterial flora, resulting in bacterial overgrowth and impeded passage of B12-IF into the bloodstream.19 A third pathway describes metformin changing the B12-IF complex by binding to it structurally.19 Each of these potential influences lessens the amount of B12 that passes through the distal ileal wall.13

Though poorly understood, low vitamin B12 levels cause a diminution of the myelin that coats the peripheral nerves, perhaps through the attenuated methylation of myelin, which subsequently disrupts the transmission of action potentials. Nonhomogeneous myelin manifests as peripheral neuropathy.8 Vitamin B12 functions as a coenzyme in the transfer of a methyl group from 5-methyl-tetrahydrofolate to tetrahydrofolate, creating methionine with the enzyme methionine synthase.20 Methionine and adenosine triphosphate are essential in assembling 5-adenosyl methionine, which is the primary methyl donor in the methylation reactions involving amines, proteins, and phospholipids (including sphingomyelin) in the myelin sheath. Thus, a deficiency of B12 leads to diminished methylation in myelin and, subsequently, the development of peripheral neuropathy.20 Once this process occurs, it is extremely difficult to reverse and correct. Low vitamin B12 levels that are symptomatic exhibit a confounding clinical similarity to diabetic peripheral neuropathy.5

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Vitamin B12 also functions as a coenzyme that connects lipid to carbohydrate metabolism in the mitochondria by converting methylmalonic acid to succinate through the enzyme methylmalonyl-coenzyme A mutase.20 A deficiency in vitamin B12 can therefore result in symptoms of malaise and fatigue.

Coexisting factors can affect the absorption of vitamin B12 in patients with T2DM. Patients who are vegetarian are known to be at risk for low vitamin B12 levels because of the absence of protein-bound vitamin B12 in plant-based foods.1 Additionally, the concomitant use of metformin with proton pump inhibitors and/or H2-antagonist medications can cause as much as a 65% and 25% reduction, respectively, in absorption of vitamin B12. This is due to the decrease in gastric hydrochloric acid, which is needed to cleave vitamin B12 from protein that is ingested.4 Similarly, alcohol use can deleteriously influence vitamin B12 levels.5

Until recently, no published guidelines existed regarding the monitoring and supplementation with exogenous cyanocobalamin, the manufactured form of vitamin B12, in patients with T2DM on long-term treatment with metformin.14,21 In 2018, the American Association of Clinical Endocrinologists and the American College of Endocrinology endorsed a comprehensive management algorithm for T2DM that calls for assessing the status of vitamin B12 levels in patients taking metformin and instituting supplementation if neuropathy develops.22