In such a scenario of secondary folate deficiency, the accumulation of methyl- and formyl-THF, which also bind and inhibit SHMT enzymes [80], could exacerbate the inability of SHMT2 to operate in the presence of the PLP-competitive inhibitor metformin (Figure 9, top panel). Here, SHMT1 is linked to hyperinsulinemic hypoglycemia, familial, 4.