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Insulin at Physiological Concentrations Selectively Activates Insulin But Not Insulin-Like Growth Factor I (IGF-I) or Insulin/IGF-I Hybrid Receptors in Endothelial Cells

Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health System, Charlottesville, Virginia 22908-1410

Address all correspondence and requests for reprints to: Zhenqi Liu, M.D., Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health System, P.O. Box 801410, Charlottesville, Virginia 22908-1410. E-mail: zl3e{at}virginia.edu.

In muscle, physiologic hyperinsulinemia, presumably acting on endothelial cells (ECs), dilates arterioles and regulates both total blood flow and capillary recruitment, which in turn influences glucose disposal. In cultured ECs, however, supraphysiological (e.g. 10 nM) insulin concentrations are typically used to study insulin receptor (IR) signaling pathways and nitric oxide generation. IGF-I receptors (IGF-IRs) are more abundant than IR in ECs, and they also respond to high concentrations of insulin. To address whether IR mediates responses to physiologic insulin stimuli, we examined the insulin concentration dependence of IR and IGF-IR-mediated insulin signaling in bovine aortic ECs (bAECs). We also assessed whether insulin/IGF-I hybrid receptors were present in bAECs. Insulin, at 100–500 pM, significantly stimulated the phosphorylation of IRß, Akt1, endothelial isoform of nitric oxide synthase, and ERK 1/2 but not the IGF-IRß subunit. At concentrations 1–5 nM or greater, insulin dose-dependently enhanced the tyrosine phosphorylation of IGF-IRß, and this was inhibited by IGF-IR neutralizing antibody. In addition, immunoprecipitation of IRß pulled down the IGF-IRß, and the IRß immunocytochemically colocalized with IGF-IRß, suggesting that ECs have insulin/IGF-I hybrid receptors. We conclude that: 1) insulin at physiological concentrations selectively activates IR signaling in bAECs; 2) bAECs express IGF-IR and insulin/IGF-I hybrid receptors in addition to IR; 3) high concentrations of insulin (1–5 nM) activate IGF-IR and hybrid receptors as well as IR; and 4) this crossover activation can confound interpretation of studies of insulin action in ECs when high insulin concentrations are used.

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