Figure 1.

Representation of candidate markers involved in a biochemical pathway related to folate metabolism, including endothelial nitric oxide synthase (NOS), serum nitrate/nitric oxide (NO), folate, and plasma total homocysteine to illustrate the proposed mechanisms of metformin-induced neuropathy.

Available vitamin B12 and folate are depleted causing a cascade of reactions that affect nerve structure (i.e. myelin) and function (i.e. blood flow: oxygen and nutrients). Active folate is reduced by metformin, resulting in less NO and, therefore, reduced blood flow to nerve. In addition, lowering folate also contributes to elevation of plasma homocysteine. Reduced B12 diminishes methylation, which inhibits homocysteine metabolism and provokes vascular endothelial damage. Moreover, reduction of folate and B12 reduces DNA/RNA synthesis, which inhibits myelin synthesis. Inability to maintain intact neuron myelin sheath reduces nerve neurotransmission and leads to neuropathy.