Download PDF
Horm Metab Res 2008; 40(9): 588-592
DOI: 10.1055/s-0028-1082325
Review

© Georg Thieme Verlag KG Stuttgart · New York

The Role of IGF-system in Vascular Insulin Resistance

H. J. Arnqvist 1 , 2
  • 1Division of Cell Biology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
  • 2Diabetes Research Centre, Faculty of Health Sciences, Linköping University, Linköping, Sweden
Further Information

Publication History

received 02.10.2007

accepted 23.01.2008

Publication Date:
15 September 2008 (online)

Also available at
    Permissions and Reprints

Abstract

Insulin and IGF-I are closely related peptides, which interact by several mechanisms. In high supraphysiological concentrations (≥10−8 M), they cross-react with each other's receptors with 100- to 1000-fold lower affinity than with their cognate receptors. This can cause confusion, since in many in vitro studies, insulin has been used in high unphysiological concentrations, which activate IGF-I receptors. Due to the differences in affinity, insulin and IGF-I probably do not activate each other's receptors in vivo. IGF-I receptors are several-fold more abundant than insulin receptors in human micro- and macrovascular endothelial cells and in human vascular smooth muscle cells. Both insulin and IGF-I receptor protein can be demonstrated and they are activated by their cognate ligand at physiological concentrations of 10−9–10−10 M. In vascular smooth muscle cells, IGF-I but not insulin stimulates metabolism and growth. IGF-I stimulates DNA-synthesis and growth in microvascular endothelial cells, but neither insulin nor IGF-I have any effect on macrovascular endothelial cells. Both insulin and IGF-I have been shown to stimulate nitric oxide production in endothelial cells, but only the effect of IGF-I was obtained at a physiological concentration. In both endothelial and vascular smooth muscle cells, insulin and IGF-I receptors occur as insulin/IGF-I hybrid receptors with high affinity to IGF-I and low for insulin. Due to the low number of insulin receptors and the presence of hybrid receptors the insulin receptor signal is probably too attenuated to elicit biological effects, explaining the insulin resistance of vascular cells in vitro. In vivo both insulin and IGF-I have been reported to increase muscle blood flow in physiological concentrations. Whether this is due to direct effects on endothelial cells or indirectly induced is not clear. The effect of insulin is attenuated by insulin resistance. In conclusion, the in vitro data suggest that endothelial cells and vascular smooth muscle cells are sensitive to IGF-I, but insensitive to insulin, and this is due to a preponderance of IGF-I receptors and the presence of insulin/IGF-I hybrid receptors.

Key words

endothelial cells - vascular smooth muscle - insulin - IGF-1 receptors

References

  • 1 Rinderknecht E, Humbel RE. The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulin.  J Biol Chem. 1978;  253 2769-2776
    PubMedGoogle Scholar
  • 2 Ullrich A, Bell JR, Chen EY, Herrera R, Petruzzelli LM, Dull TJ, Gray A, Coussens L, Liao YC, Tsubokawa M, Mason A, Seeburg PH, Grunfeld C, Rosen OM, Ramachandran J. Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes.  Nature. 1985;  313 756-761
    CrossrefPubMedGoogle Scholar
  • 3 Ullrich A, Gray A, Tam AW, Yang-Feng T, Tsubokawa M, Collins C, Henzel W, Le-Bon T, Kathuria S, Chen E. Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity.  EMBO J. 1986;  5 2503-2512
    PubMedGoogle Scholar
  • 4 Moxham CP, Duronio V, Jacobs S. Insulin-like growth factor I receptor beta-subunit heterogeneity. Evidence for hybrid tetramers composed of insulin-like growth factor I and insulin receptor heterodimers.  J Biol Chem. 1989;  264 13238-13244
    PubMedGoogle Scholar
  • 5 Soos MA, Siddle K. Immunological relationships between receptors for insulin and insulin-like growth factor I. Evidence for structural heterogeneity of insulin-like growth factor I receptors involving hybrids with insulin receptors.  Biochem J. 1989;  263 553-563
    PubMedGoogle Scholar
  • 6 Möller C, Arner P, Sonnenfeld T, Norstedt G. Quantitative comparison of insulin-like growth factor mRNA levels in human and rat tissues analysed by a solution hybridization assay.  J Mol Endocrinol. 1991;  7 213-222
    CrossrefPubMedGoogle Scholar
  • 7 Brismar K, Fernqvist-Forbes E, Wahren J, Hall K. Effect of insulin on the hepatic production of insulin-like growth factor-binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes.  J Clin Endocrinol Metab. 1994;  79 872-878
    CrossrefPubMedGoogle Scholar
  • 8 Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions.  Endocr Rev. 1995;  16 3-34
    CrossrefPubMedGoogle Scholar
  • 9 Frystyk J. Free insulin-like growth factors measurements and relationships to growth hormone secretion and glucose homeostasis.  Growth Horm IGF Res. 2004;  14 337-375
    CrossrefPubMedGoogle Scholar
  • 10 Kim JJ, Accili D. Signalling through IGF-I and insulin receptors: where is the specificity?.  Growth Horm IGF Res. 2002;  12 84-90
    CrossrefPubMedGoogle Scholar
  • 11 Bar RS, Hoak JC, Peacock ML. Insulin receptors in human endothelial cells: identification and characterization.  J Clin Endocrinol Metab. 1978;  47 699-702
    CrossrefPubMedGoogle Scholar
  • 12 King GL, Buzney SM, Kahn CR, Hetu N, Buchwald S, Macdonald SG, Rand LI. Differential responsiveness to insulin of endothelial and support cells from micro- and macrovessels.  J Clin Invest. 1983;  71 974-979
    CrossrefPubMedGoogle Scholar
  • 13 Zeng G, Quon MJ. Insulin-stimulated production of nitric oxide is inhibited by wortmannin, direct measurement in vascular endothelial cells.  J Clin Invest. 1996;  98 894-898
    CrossrefPubMedGoogle Scholar
  • 14 Dekker Nitert M, Chisalita SI, Olsson K, Bornfeldt KE, Arnqvist HJ. IGF-I/Insulin Hybrid Receptors in Human Endothelial Cells.  Mol Cell Endocrinol. 2005;  229 31-37
    CrossrefPubMedGoogle Scholar
  • 15 Aljada A, Ghanim H, Assian E, Dandona P. Tumor necrosis factor-alpha inhibits insulin-induced increase in endothelial nitric oxide synthase and reduces insulin receptor content and phosphorylation in human aortic endothelial cells.  Metabolism. 2002;  51 487-491
    CrossrefPubMedGoogle Scholar
  • 16 Federici M, Menghini R, Mauriello A, Hribal ML, Ferrelli F, Lauro D, Sbraccia P, Spagnoli LG, Sesti G, Lauro R. Insulin-dependent activation of endothelial nitric oxide synthase is impaired by O-linked glycosylation modification of signaling proteins in human coronary endothelial cells.  Circulation. 2002;  106 466-472
    CrossrefPubMedGoogle Scholar
  • 17 Salt IP, Morrow VA, Brandie FM, Connell JM, Petrie JR. High glucose inhibits insulin-stimulated nitric oxide production without reducing endothelial nitric-oxide synthase Ser1177 phosphorylation in human aortic endothelial cells.  J Biol Chem. 2003;  278 18791-18797
    CrossrefPubMedGoogle Scholar
  • 18 Chisalita SI, Dekker-Nitert M, Arnqvist HJ. Characterisation of receptors for insulin-like growth factor-I and insulin in human coronary artery endothelial cells.  Growth Horm IGF Res. 2006;  16 258-266
    CrossrefPubMedGoogle Scholar
  • 19 Chisalita SI, Arnqvist HJ. Insulin-like growth factor-I receptors are more abundant than insulin receptors in human micro- and macrovascular endothelial cells.  Am J Physiol. 2004;  286 E896-E901
    CrossrefPubMedGoogle Scholar
  • 20 Banskota NK, Taub R, Zellner K, Olsen P, King GL. Characterization of induction of protooncogene c-myc and cellular growth in human vascular smooth muscle cells by insulin and IGF-I.  Diabetes. 1989;  38 123-129
    CrossrefPubMedGoogle Scholar
  • 21 Arnqvist HJ, Bornfeldt KE, Chen Y, Lindström T. The IGF-system in vascular smooth muscle; Interaction with insulin and growth factors.  Metabolism. 1995;  44 ((Suppl 4)) 58-66
    CrossrefPubMedGoogle Scholar
  • 22 Avena R, Mitchell ME, Carmody B, Arora S, Neville RF, Sidaway AN. Insulin-like growth factor-1 receptors mediate infragenicular vascular smooth muscle cell proliferation in response to glucose and insulin not by insulin receptors.  Am J Surg. 1999;  178 156-161
    CrossrefPubMedGoogle Scholar
  • 23 Ward CW, Lawrence MC, Streltsov VA, Adams TE, MacKern NM. The insulin and EGF receptor structures: new insights into ligand-induced receptor activation.  Trends Biochem Sci. 2007;  32 129-137
    CrossrefPubMedGoogle Scholar
  • 24 Dupont J, Dunn SE, Barrett JC, LeRoith D. Microarray analysis and identification of novel molecules involved in insulin-like growth factor-1 receptor signaling and gene expression.  Recent Prog Horm Res. 2003;  58 325-342
    CrossrefPubMedGoogle Scholar
  • 25 Andreozzi F, Laratta E, Procopio C, Hribal ML, Sciacqua A, Perticone M, Miele C, Perticone F, Sesti G. Interleukin-6 impairs the insulin signaling pathway, promoting production of nitric oxide in human umbilical vein endothelial cells.  Mol Cell Biol. 2007;  27 2372-2383
    CrossrefPubMedGoogle Scholar
  • 26 Konopatskaya O, Shore AC, Tooke JE, Whatmore J. A role for heterotrimeric GTP-binding proteins and ERK1/2 in insulin-mediated, nitric-oxide-dependent, cyclic GMP production in human umbilical vein endothelial cells.  Diabetologia. 2005;  48 595-604
    CrossrefPubMedGoogle Scholar
  • 27 Tsukahara H, Gordienko DV, Tonshoff B, Gelato MC, Goligorsky MS. Direct demonstration of insulin-like growth factor-I-induced nitric oxide production by endothelial cells.  Kidney Int. 1994;  45 598-604
    CrossrefPubMedGoogle Scholar
  • 28 Staiger K, Staiger H, Schweitzer MA, Metzinger E, Balletshofer B, Häring HU, Kellerer M. Insulin and its analogue glargine do not affect viability and proliferation of human coronary artery endothelial and smooth muscle cells.  Diabetologia. 2005;  48 1898-1905
    CrossrefPubMedGoogle Scholar
  • 29 Artwohl M, Brunmair B, Furnsinn C, Holzenbein T, Rainer G, Freudenthaler A, Porod EM, Huttary N, Baumgartner-Parzer SM. Insulin does not regulate glucose transport and metabolism in human endothelium.  Eur J Clin Invest. 2007;  37 643-650
    CrossrefPubMedGoogle Scholar
  • 30 Mann GE, Yudilevich DL, Sobrevia L. Regulation of amino acid and glucose transporters in endothelial and smooth muscle cells.  Physiol Rev. 2003;  83 183-252
    PubMedGoogle Scholar
  • 31 Giannini S, Cresci B, Pala L, Ciucci A, Franchini A, Manuelli C, Fujita-Yamaguchi Y, Cappugi P, Zonefrati R, Rotella CM. IGFBPs modulate IGF-I- and high glucose-controlled growth of human retinal endothelial cells.  J Endocrinol. 2001;  171 273-284
    CrossrefPubMedGoogle Scholar
  • 32 Chisalita SI, Arnqvist HJ. Expression and function of receptors for insulin-like growth factor-I and insulin in human coronary artery smooth muscle cells.  Diabetologia. 2005;  48 2155-2161
    CrossrefPubMedGoogle Scholar
  • 33 Patel VA, Zhang QJ, Siddle K, Soos MA, Goddard M, Weissberg PL, Bennett MR. Defect in insulin-like growth factor-1 survival mechanism in atherosclerotic plaque-derived vascular smooth muscle cells is mediated by reduced surface binding and signaling.  Circ Res. 2001;  88 895-902
    CrossrefPubMedGoogle Scholar
  • 34 Delafontaine P. Insulin-like growth factor I and its binding proteins in the cardiovascular system.  Cardiovasc Res. 1995;  30 825-834
    PubMedGoogle Scholar
  • 35 Johansson GS, Arnqvist HJ. 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. 2006;  291 E1124-E1130
    CrossrefPubMedGoogle Scholar
  • 36 Soos MA, Field CE, Siddle K. Purified hybrid insulin/insulin-like growth factor-I receptors bind insulin-like growth factor-I, but not insulin, with high affinity.  Biochem J. 1993;  290 419-426
    PubMedGoogle Scholar
  • 37 Meyts P De, Whittaker J. Structural biology of insulin and IGF1 receptors: implications for drug design.  Nat Rev Drug Discov. 2002;  1 769-783
    CrossrefPubMedGoogle Scholar
  • 38 Moller DE, Yokota A, Caro JF, Flier JS. Tissue-specific expression of two alternatively spliced insulin receptor mRNAs in man.  Mol Endocrinol. 1989;  3 1263-1269
    CrossrefPubMedGoogle Scholar
  • 39 Mosthaf L, Grako K, Dull TJ, Coussens L, Ullrich A, MacClain DA. Functionally distinct insulin receptors generated by tissue-specific alternative splicing.  EMBO J. 1990;  9 2409-2413
    PubMedGoogle Scholar
  • 40 Frasca F, Pandini G, Scalia P, Sciacca L, Mineo R, Costantino A, Goldfine ID, Belfiore A, Vigneri R. Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells.  Mol Cell Biol. 1999;  19 3278-3288
    PubMedGoogle Scholar
  • 41 Pandini G, Frasca F, Mineo R, Sciacca L, Vigneri R, Belfiore A. Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved.  J Biol Chem. 2002;  277 39684-39695
    CrossrefPubMedGoogle Scholar
  • 42 Slaaby R, Schäffer L, Lautrup-Larsen I, Andersen AS, Shaw AC, Mathiasen IS, Brandt J. 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. 2006;  281 25869-25874
    CrossrefPubMedGoogle Scholar
  • 43 Benyoucef S, Surinya KH, Hadaschik D, Siddle K. Characterization of insulin/IGF hybrid receptors: contributions of the insulin receptor L2 and Fn1 domains and the alternatively spliced exon 11 sequence to ligand binding and receptor activation.  Biochem J. 2007;  403 603-613
    CrossrefPubMedGoogle Scholar
  • 44 Pandini G, Vigneri R, Costantino A, Frasca F, Ippolito A, Fujita-Yamaguchi Y, Siddle K, Goldfine ID, Belfiore A. Insulin and insulin-like growth factor-I (IGF-I) receptor overexpression in breast cancers leads to insulin/IGF-I hybrid receptor overexpression: evidence for a second mechanism of IGF-I signaling.  Clin Cancer Res. 1999;  5 1935-1944
    PubMedGoogle Scholar
  • 45 Gelfand RA, Barrett EJ. Effect of physiologic hyperinsulinemia on skeletal muscle protein synthesis and breakdown in man.  J Clin Invest. 1987;  80 1-6
    CrossrefPubMedGoogle Scholar
  • 46 Laakso M, Edelman SV, Brechtel G, Baron AD. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance.  J Clin Invest. 1990;  85 1844-1852
    CrossrefPubMedGoogle Scholar
  • 47 Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release.  J Clin Invest. 1994;  94 1172-1179
    CrossrefPubMedGoogle Scholar
  • 48 Serné EH, IJzerman RG, Gans RO, Nijveldt R, Vries G De, Evertz R, Donker AJ, Stehouwer CD. Direct evidence for insulin-induced capillary recruitment in skin of healthy subjects during physiological hyperinsulinemia.  Diabetes. 2002;  51 1515-1522
    CrossrefPubMedGoogle Scholar
  • 49 Kim F, Tysseling KA, Rice J, Pham M, Haji L, Gallis BM, Baas AS, Paramsothy P, Giachelli CM, Corson MA, Raines EW. Free fatty acid impairment of nitric oxide production in endothelial cells is mediated by IKKbeta.  Arterioscler Thromb Vasc Biol. 2005;  25 989-994
    CrossrefPubMedGoogle Scholar
  • 50 Pendergrass M, Fazioni E, Collins D, DeFronzo RA. IGF-I increases forearm blood flow without increasing forearm glucose uptake.  Am J Physiol. 1998;  275 E345-E350
    PubMedGoogle Scholar
  • 51 Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance.  J Clin Invest. 2006;  116 1793-1801
    CrossrefPubMedGoogle Scholar
  • 52 Wei Y, Chen K, Whaley-Connell AT, Stump CS, Ibdah JA, Sowers JR. Skeletal muscle insulin resistance: role of inflammatory cytokines and reactive oxygen species.  Am J Physiol Regul Integr Comp Physiol. 2008;  294 R673-R680
    CrossrefPubMedGoogle Scholar
  • 53 Jiang ZY, Lin YW, Clemont A, Feener EP, Hein KD, Igarashi M, Yamauchi T, White MF, King GL. Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats.  J Clin Invest. 1999;  104 447-457
    CrossrefPubMedGoogle Scholar
  • 54 Gosmanov AR, Stentz FB, Kitabchi AE. De novo emergence of insulin-stimulated glucose uptake in human aortic endothelial cells incub-ated with high glucose.  Am J Physiol Endocrinol Metab. 2006;  290 E516-E522
    PubMedGoogle Scholar
  • 55 Rask-Madsen C, King GL. Mechanisms of Disease: endothelial dysfunction in insulin resistance and diabetes.  Nat Clin Pract Endocrinol Metab. 2007;  1 46-56
    PubMedGoogle Scholar
  • 56 Cusi K, DeFronzo R. Recombinant human insulin-like growth factor I treatment for 1 week improves metabolic control in type 2 diabetes by ameliorating hepatic and muscle insulin resistance.  J Clin Endocrinol Metab. 2000;  85 3077-3084
    CrossrefPubMedGoogle Scholar
  • 57 Froesch ER, Ze D, Hussain MP. Metabolic and therapeutic effects of insulin-like growth factor I.  Horm Res. 1994;  42 66-71
    CrossrefPubMedGoogle Scholar
  • 58 Hanaire-Broutin H, Sallerin-Caute B, Poncet MF, Tauber M, Bastide R, Rosenfeld R, Tauber JP. Insulin therapy and GH-IGF-I axis disorders in diabetes: impact of glycaemic control and hepatic insulinization.  Diabetes Metab. 1996;  22 245-250
    PubMedGoogle Scholar

Correspondence

H. J. ArnqvistMD, PhD 

Department of Clinical and Experimental Medicine

Division of Cell Biology

University Hospital

581 85 Linköping

Sweden

Phone: +46/13/22 27 89

Fax: +46/13/22 42 73

Email: hans.arnqvist@ibk.liu.se