This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Li, G. Articles by Liu, Z. Search for Related Content PubMed PubMed Citation Articles by Li, G. Articles by Liu, Z.

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.

This article has been cited by other articles:

				G. E. Lim, G. J. Huang, N. Flora, D. LeRoith, C. J. Rhodes, and P. L. Brubaker Insulin Regulates Glucagon-Like Peptide-1 Secretion from the Enteroendocrine L Cell Endocrinology, February 1, 2009; 150(2): 580 - 591. [Abstract] [Full Text] [PDF]

				S. Erbel, C. Reers, V. W. Eckstein, J. Kleeff, M. W. Buchler, P. P. Nawroth, and R. A. Ritzel Proliferation of Colo-357 Pancreatic Carcinoma Cells and Survival of Patients With Pancreatic Carcinoma Are Not Altered by Insulin Glargine Diabetes Care, June 1, 2008; 31(6): 1105 - 1111. [Abstract] [Full Text] [PDF]

				G. Li, J.-P. del Rincon, L. A. Jahn, Y. Wu, B. Gaylinn, M. O. Thorner, and Z. Liu Growth Hormone Exerts Acute Vascular Effects Independent of Systemic or Muscle Insulin-like Growth Factor I J. Clin. Endocrinol. Metab., April 1, 2008; 93(4): 1379 - 1385. [Abstract] [Full Text] [PDF]

				C. Lotton, D. Rodrigue, C. Elie, A. Rothenbuhler, N. Lahlou, C. Le Stunff, and P. Bougneres Akt Phosphorylation in Lymphocytes Provides an Index of in Vitro Insulin-Like Growth Factor I Sensitivity Associated with Growth Hormone-Induced Growth J. Clin. Endocrinol. Metab., April 1, 2008; 93(4): 1458 - 1463. [Abstract] [Full Text] [PDF]

				H. Wang, A. X. Wang, Z. Liu, and E. J. Barrett Insulin Signaling Stimulates Insulin Transport by Bovine Aortic Endothelial Cells Diabetes, March 1, 2008; 57(3): 540 - 547. [Abstract] [Full Text] [PDF]

				U. Hiden, E. Glitzner, M. Ivanisevic, J. Djelmis, C. Wadsack, U. Lang, and G. Desoye MT1-MMP Expression in First-Trimester Placental Tissue Is Upregulated in Type 1 Diabetes as a Result of Elevated Insulin and Tumor Necrosis Factor-{alpha} Levels Diabetes, January 1, 2008; 57(1): 150 - 157. [Abstract] [Full Text] [PDF]

				L. Wang, T. C. Schulz, E. S. Sherrer, D. S. Dauphin, S. Shin, A. M. Nelson, C. B. Ware, M. Zhan, C.-Z. Song, X. Chen, et al. Self-renewal of human embryonic stem cells requires insulin-like growth factor-1 receptor and ERBB2 receptor signaling Blood, December 1, 2007; 110(12): 4111 - 4119. [Abstract] [Full Text] [PDF]

				Z. Liu Insulin at physiological concentrations increases microvascular perfusion in human myocardium Am J Physiol Endocrinol Metab, November 1, 2007; 293(5): E1250 - E1255. [Abstract] [Full Text] [PDF]

				E. R. Duncan, S. J. Walker, V. A. Ezzat, S. B. Wheatcroft, J.-M. Li, A. M. Shah, and M. T. Kearney Accelerated endothelial dysfunction in mild prediabetic insulin resistance: the early role of reactive oxygen species Am J Physiol Endocrinol Metab, November 1, 2007; 293(5): E1311 - E1319. [Abstract] [Full Text] [PDF]

				R. Muniyappa, M. Montagnani, K. K. Koh, and M. J. Quon Cardiovascular Actions of Insulin Endocr. Rev., August 1, 2007; 28(5): 463 - 491. [Abstract] [Full Text] [PDF]

				G. Li, E. J. Barrett, M. O. Barrett, W. Cao, and Z. Liu Tumor Necrosis Factor-{alpha} Induces Insulin Resistance in Endothelial Cells via a p38 Mitogen-Activated Protein Kinase-Dependent Pathway Endocrinology, July 1, 2007; 148(7): 3356 - 3363. [Abstract] [Full Text] [PDF]

				A. Denley, J. M. Carroll, G. V. Brierley, L. Cosgrove, J. Wallace, B. Forbes, and C. T. Roberts Jr. Differential Activation of Insulin Receptor Substrates 1 and 2 by Insulin-Like Growth Factor-Activated Insulin Receptors Mol. Cell. Biol., May 15, 2007; 27(10): 3569 - 3577. [Abstract] [Full Text] [PDF]

				W. Chai and Z. Liu p38 Mitogen-Activated Protein Kinase Mediates Palmitate-Induced Apoptosis But Not Inhibitor of Nuclear Factor-{kappa}B Degradation in Human Coronary Artery Endothelial Cells Endocrinology, April 1, 2007; 148(4): 1622 - 1628. [Abstract] [Full Text] [PDF]

				A. Fischoeder, H. Meyborg, D. Stibenz, E. Fleck, K. Graf, and P. Stawowy Insulin augments matrix metalloproteinase-9 expression in monocytes Cardiovasc Res, March 1, 2007; 73(4): 841 - 848. [Abstract] [Full Text] [PDF]

				G. S. Johansson and H. J. Arnqvist Insulin and IGF-I action on insulin receptors, IGF-I receptors, and hybrid insulin/IGF-I receptors in vascular smooth muscle cells Am J Physiol Endocrinol Metab, November 1, 2006; 291(5): E1124 - E1130. [Abstract] [Full Text] [PDF]

				R. Slaaby, L. Schaffer, I. Lautrup-Larsen, A. S. Andersen, A. C. Shaw, I. S. Mathiasen, and J. Brandt Hybrid Receptors Formed by Insulin Receptor (IR) and Insulin-like Growth Factor I Receptor (IGF-IR) Have Low Insulin and High IGF-1 Affinity Irrespective of the IR Splice Variant J. Biol. Chem., September 8, 2006; 281(36): 25869 - 25874. [Abstract] [Full Text] [PDF]

				J Ogino, K Sakurai, K Yoshiwara, Y. Suzuki, N Ishizuka, N Seki, Y. Suzuki, H Koseki, T Shirasawa, N Hashimoto, et al. Insulin resistance and increased pancreatic {beta}-cell proliferation in mice expressing a mutant insulin receptor (P1195L). J. Endocrinol., September 1, 2006; 190(3): 739 - 747. [Abstract] [Full Text] [PDF]

				H. Wang, Z. Liu, G. Li, and E. J. Barrett The vascular endothelial cell mediates insulin transport into skeletal muscle Am J Physiol Endocrinol Metab, August 1, 2006; 291(2): E323 - E332. [Abstract] [Full Text] [PDF]

				A. R. Gosmanov, F. B. Stentz, and A. E. Kitabchi De novo emergence of insulin-stimulated glucose uptake in human aortic endothelial cells incubated with high glucose Am J Physiol Endocrinol Metab, March 1, 2006; 290(3): E516 - E522. [Abstract] [Full Text] [PDF]