INSR and hyperinsulinism: Hyperinsulinemia has been shown to increase hepatic production and bioavailability of IGFI, in part by inhibiting hepatic production of IGF binding proteins 1 and 2 (IGFBP1 and IGFBP2), which sequester IGFs in the serum.90, 91 This excess IGFI may hyperactivate IGF1R and INSR/IGFIR and their proliferative and anti-apoptotic programs in both premalignant and malignant tissues.