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Effects of Insulin on Prenylation as a Mechanism of Potentially Detrimental Influence of Hyperinsulinemia¹

Research Service of the Department of Veterans Affairs, Denver Veterans Affairs Medical Center, Department of Medicine, University of Colorado Health Sciences Center (B.D., I.G., R.S., K.W., M.G.), Denver, Colorado 80220; San Diego Veterans Affairs Medical Center, and Department of Medicine, University of California (P.M., Y.K., J.O.), San Diego, California 92161; Department of Nutrition, Case Western Reserve University School of Medicine (J.F.), Cleveland, Ohio 44106; Diabetes Branch (M.R.) and Developmental Endocrinology Branch (D.A.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; and Veterans Affairs Medical Center and Department of Medicine, University of Mississippi Medical Center (R.C., D.M.), Jackson, Mississippi 39216

Address all correspondence and requests for reprints to: Dr. Boris Draznin, Veterans Affairs Medical Center (151), 1055 Clermont Street, Denver, Colorado 80220. E-mail: drazninb{at}den-res.org

To investigate the cause and effect relationship between hyperinsulinemia and the increased amounts of farnesylated p21Ras, we performed hyperinsulinemic euglycemic clamps in normal weight volunteers as well as in normal mice and dogs. Insulin infusions significantly raised the amounts of farnesylated p21Ras in the white blood cells of humans, in liver samples of mice and dogs, and in aorta samples of mice. Obese hyperinsulinemic individuals and dogs (made hyperinsulinemic by surgical diversion of the pancreatic outflow from the portal vein into the vena cava) displayed increased amounts of farnesylated p21Ras before the hyperinsulinemic clamps. Infusions of insulin did not alter the already increased levels of farnesylated p21Ras in these experimental models.

To further investigate the role of acquired insulin resistance in modulating insulin’s effect on p21Ras prenylation, we induced insulin resistance in rats by glucosamine infusion. Insulin-resistant glucosamine-treated animals displayed significantly increased farnesylated p21Ras in response to insulin infusion compared to that in control saline-treated animals. Transgenic models of insulin resistance (heterozygous insulin receptor substrate-1 knockout mice, A-ZIP/F-1 fatless mice, and animals overexpressing glutamine:fructose-6-phosphate amidotransferase) contained increased amounts of farnesylated p21Ras.

We conclude that hyperinsulinemia, either endogenous (a prominent feature of insulin resistance) or produced by infusions of insulin, increases the amounts of farnesylated p21Ras in humans, mice, and dogs. This aspect of insulin action may represent one facet of the molecular mechanism of the potentially detrimental influence of hyperinsulinemia.

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