Long-term metformin therapy and vitamin B12 deficiency: An association to bear in mind

Figure 1 Postulated mechanisms accounting for metformin-induced vitamin B12 deficiency. Metformin may cause vitamin B12 deficiency through one or more of the following mechanisms: (1) Interference with the calcium-dependent binding of the intrinsic factor (IF)-vitamin B12 complex to the cubilin receptor on enterocytes at the ileum level and/or interaction with the cubilin endocytic receptor; (2) Alteration in bile acid metabolism and reabsorption, resulting in impaired enterohepatic circulation of vitamin B12; (3) Reduced IF secretion by gastric parietal cells; (4) Increased liver accumulation of vitamin B12, resulting in altered tissue distribution and metabolism of vitamin B12; and (5) Alteration in small intestine motility, resulting in small intestinal bacterial overgrowth and subsequent inhibition of IF-vitamin B12 complex absorption in the distal ileum. B12: Vitamin B12; BAs: Bile acids; IF: Intrinsic factor.