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Hyperinsulinemia Potentiates Activation of p21Ras by Growth Factors

Medical Research Service and the Department of Medicine, Veterans Affairs Medical Center and the University of Colorado Health Sciences Center, Denver, Colorado 80220

Address correspondence and requests for reprints to: Boris Draznin, M.D., Ph.D., University of Colorado Health Sciences Center, Department of Medicine, VA Hospital, 111 H, 1055 Clermont Street, Denver, Colorado 80220.

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. Effect of hyperinsulinemia were completely abolished by the presence of 1 µM -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.

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