Additional calculated metformin-induced changes supported by previous results include: (i) a downregulation of folate metabolism consistent with reported folate deficiency in metformin-treated patients30, (ii) upregulated oxidative stress response consistent with reported lower reactive oxygen species levels31 and (iii) increased polyamine synthesis and recycling pathways that may result from shared use of organic cation transport (OCT) proteins between metformin32 and polyamines33. Here, PLXNA2 is linked to folate deficiency.