INS and hyperinsulinism: Other proposed mechanisms that may account for the anticancer action of metformin appear to be indirect, probably dependent on the metformin-induced reduction of plasma glucose and insulin levels and its beneficial effects on some IR mitogenic biomarkers, such as IGF1 and IGFBP3 [322], leading to decreased activation of INSR (and INSR/IGF1R hybrid receptors) and attenuation of growth and proliferation of a subset of tumors for which chronic hyperinsulinemia may offer a growth advantage.