title: Inhibition of phosphatidylinositol 3-kinase enhances mitogenic actions of insulin in endothelial cells.
abstract: The concept of "selective insulin resistance" has emerged as a unifying hypothesis in attempts to reconcile the influence of insulin resistance with that of hyperinsulinemia in the pathogenesis of macrovascular complications of diabetes. To explore this hypothesis in endothelial cells, we designed a set of experiments to mimic the "typical metabolic insulin resistance" by blocking the phosphatidylinositol 3-kinase pathway and exposing the cells to increasing concentrations of insulin ("compensatory hyperinsulinemia"). Inhibition of phosphatidylinositol 3-kinase with wortmannin blocked the ability of insulin to stimulate increased expression of endothelial nitric-oxide synthase, did not affect insulin-induced activation of MAP kinase, and increased the effects of insulin on prenylation of Ras and Rho proteins. At the same time, this experimental paradigm resulted in increased expression of vascular cellular adhesion molecules-1 and E-selectin, as well as increased rolling interactions of monocytes with endothelial cells. We conclude that inhibition of the metabolic branch of insulin signaling leads to an enhanced mitogenic action of insulin in endothelial cells.
authors.affiliation: Cardiology Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Montagnani
authors.forename: Inga
authors.initials: I
authors.lastname: Golovchenko
authors.forename: Injune
authors.initials: I
authors.lastname: Kim
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
authors.forename: Marc L
authors.initials: ML
authors.lastname: Goalstone
authors.forename: Ameya N
authors.initials: AN
authors.lastname: Mundhekar
authors.forename: Mette
authors.initials: M
authors.lastname: Johansen
authors.forename: Dennis F
authors.initials: DF
authors.lastname: Kucik
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Quon
authors.forename: Boris
authors.initials: B
authors.lastname: Draznin
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D002478:Cells, Cultured; D003925:Diabetic Angiopathies / Q000209:etiology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008934:Mitogens / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D004791:Enzyme Inhibitors; D007328:Insulin; D008934:Mitogens; D000081082:Phosphoinositide-3 Kinase Inhibitors; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D020928:Mitogen-Activated Protein Kinases; D000077191:Wortmannin