INS and hyperinsulinism: Since insulin with 40–80% homology to the insulin-like growth factor-1 (IGF-1) [40] and IGF-1R with a 70% homology to the IR [41], in the condition of hyperinsulinemia, insulin can overcome the restriction of lower affinity to the IGF-1R and activate the downstream signaling of the IRS/PI3K/Akt and Ras/Raf/extracellular-signal-regulated kinase (ERK) pathways, thus augments its mitogenic and antiapoptotic effects [42–44].