Hyperinsulinemia potentiates activation of p21Ras by growth factors

Incubation of 3T3-L1 fibroblasts with insulin (10 nM or 100 nM) for 24 or 48 hours resulted in a significant increase in the amount of farnesylated p21Ras with a concomitant increase in the amount of GTP-loaded p21Ras. Cells preincubated with 100 nM insulin for 24 or 48 hours exhibited further 5-8 fold increases in p21Ras.GTP loading in response to an acute (10 minute) challenge with either insulin, EGF, or IGF-1. Effects of hyperinsulinemia were completely abolished by the presence of 1 microM alpha-hydroxyfarnesylphosphonic acid, a potent inhibitor of farnesyltransferase. These novel observations indicate that hyperinsulinemia increases the cellular pool of farnesylated p21Ras and thereby potentiates activation of p21Ras by growth factors.