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Insulin-Like Growth Factors and Their Binding Proteins: Biological Actions^*

Division of Endocrinology, Department of Medicine, University of North Carolina Chapel Hill, North Carolina 27599-7170

Abstract

I. Introduction: THE insulin-like growth factors were discovered on the basis of their ability to stimulate cartilage sulfation and to replace the "sulfation factor activity" of GH, as determined using an in vivo assay, in an in vitro test system (1). The biological significance of this finding was quickly expanded beyond the study of cartilage sulfation to include stimulation of DNA synthesis (2), proteoglycan synthesis (3), glycosaminoglycan synthesis (4), and protein synthesis (5). Most of these studies used tissue preparations such as isolated diaphragm, cartilage, or epididymal fat pads to study biologicalactivity. In recognition of its generalized pleiotypic actions, in the early 1970's sulfation factor was renamed somatomedin (mediator of the effects of somatotropin) and was included in the emerging classification of broad spectrum growth factors along with platelet derived growth factor, fibroblast growth factor, and epidermal growth factor (6). During the period in which the biological actions of sulfation factor were being characterized, parallel studies were initiated that attempted to define factors in serum that could stimulate insulin-like effects. Because these factors were known to be distinct from immunoreactive insulin, their bioassay was based on insulin-like actions that could not be abolished by the simultaneous addition of anti-insulin antibody, and the factors were termed nonsuppressible insulin-like activity (NSILA) (7). Initial biological studies of both NSILA and somatomedin were based on the use of crude serum extracts. Early attempts to extract these factors from tissues were generally not successful, and by 1970 it had been concluded that no concentrated organ source for them existed (8). However, highly purified preparations of both factors were prepared from serum extracts.

Footnotes

^* Supported in part by NIH Grants DK-02024 (to J.I.J.) and AG–02331(to D.R.C.).

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				R. D. Clugston, W. Zhang, and J. J. Greer Gene expression in the developing diaphragm: significance for congenital diaphragmatic hernia Am J Physiol Lung Cell Mol Physiol, April 1, 2008; 294(4): L665 - L675. [Abstract] [Full Text] [PDF]

				C. Iosef, T. Gkourasas, C. Y. H. Jia, S. S.-C. Li, and V. K. M. Han A Functional Nuclear Localization Signal in Insulin-Like Growth Factor Binding Protein-6 Mediates Its Nuclear Import Endocrinology, March 1, 2008; 149(3): 1214 - 1226. [Abstract] [Full Text] [PDF]

				T. Yokota, H. Shimokawa, S. Shibata, K. Itoh, Y. Baba, K. Ohya, K. Ohyama, and S. Suzuki Insulin-like Growth Factor I Regulates Apoptosis in Condylar Cartilage Journal of Dental Research, February 1, 2008; 87(2): 159 - 163. [Abstract] [Full Text] [PDF]

				S. Denger, T. Bahr-Ivacevic, H. Brand, G. Reid, J. Blake, M. Seifert, C.-Y. Lin, K. May, V. Benes, E. T. Liu, et al. Transcriptome Profiling of Estrogen-Regulated Genes in Human Primary Osteoblasts Reveals an Osteoblast-Specific Regulation of the Insulin-Like Growth Factor Binding Protein 4 Gene Mol. Endocrinol., February 1, 2008; 22(2): 361 - 379. [Abstract] [Full Text] [PDF]

				M A Fenwick, S Llewellyn, R Fitzpatrick, D A Kenny, J J Murphy, J Patton, and D C Wathes Negative energy balance in dairy cows is associated with specific changes in IGF-binding protein expression in the oviduct Reproduction, January 1, 2008; 135(1): 63 - 75. [Abstract] [Full Text] [PDF]

				F. Y. Obese, S. Humphrys, K. L. Macmillan, and A. R. Egan Measuring Concentrations of Insulin-Like Growth Factor-I with an Enzyme-Linked Immunosorbent Antibody Assay in Plasma Samples from Holstein Cows J Dairy Sci, January 1, 2008; 91(1): 160 - 168. [Abstract] [Full Text] [PDF]

				P. D. Ryan and P. E. Goss The Emerging Role of the Insulin-Like Growth Factor Pathway as a Therapeutic Target in Cancer Oncologist, January 1, 2008; 13(1): 16 - 24. [Abstract] [Full Text] [PDF]

				J. W. B de Groot, B. Rikhof, J. van Doorn, H. J G Bilo, M. A Alleman, A. H Honkoop, and W. T A van der Graaf Non-islet cell tumour-induced hypoglycaemia: a review of the literature including two new cases Endocr. Relat. Cancer, December 1, 2007; 14(4): 979 - 993. [Abstract] [Full Text] [PDF]

				N. Shved, G. Berishvili, H. D'Cotta, J.-F. Baroiller, H. Segner, E. Eppler, and M. Reinecke Ethinylestradiol differentially interferes with IGF-I in liver and extrahepatic sites during development of male and female bony fish J. Endocrinol., December 1, 2007; 195(3): 513 - 523. [Abstract] [Full Text] [PDF]

				M. Johansson, J. D. McKay, F. Wiklund, S. Rinaldi, M. Verheus, C. H. van Gils, G. Hallmans, K. Balter, H.-O. Adami, H. Gronberg, et al. Implications for Prostate Cancer of Insulin-Like Growth Factor-I (IGF-I) Genetic Variation and Circulating IGF-I Levels J. Clin. Endocrinol. Metab., December 1, 2007; 92(12): 4820 - 4826. [Abstract] [Full Text] [PDF]

				S. A. Kaplan and P. Cohen REVIEW: The Somatomedin Hypothesis 2007: 50 Years Later J. Clin. Endocrinol. Metab., December 1, 2007; 92(12): 4529 - 4535. [Abstract] [Full Text] [PDF]

				M. S. Gulay, M. Liboni, M. J. Hayen, and H. H. Head Supplementing Holstein Cows with Low Doses of Bovine Somatotropin Prepartum and Postpartum Reduces Calving-Related Diseases J Dairy Sci, December 1, 2007; 90(12): 5439 - 5445. [Abstract] [Full Text] [PDF]

				K. E. Govoni, J. E. Wergedal, L. Florin, P. Angel, D. J. Baylink, and S. Mohan Conditional Deletion of Insulin-Like Growth Factor-I in Collagen Type 1{alpha}2-Expressing Cells Results in Postnatal Lethality and a Dramatic Reduction in Bone Accretion Endocrinology, December 1, 2007; 148(12): 5706 - 5715. [Abstract] [Full Text] [PDF]

				M. Rehage, S. Mohan, J. E. Wergedal, B. Bonafede, K. Tran, D. Hou, D. Phang, A. Kumar, and X. Qin Transgenic Overexpression of Pregnancy-Associated Plasma Protein-A Increases the Somatic Growth and Skeletal Muscle Mass in Mice Endocrinology, December 1, 2007; 148(12): 6176 - 6185. [Abstract] [Full Text] [PDF]

				A. Vrieling, D. W Voskuil, J. M Bonfrer, C. M Korse, J. van Doorn, A. Cats, A. C Depla, R. Timmer, B. J Witteman, F. E van Leeuwen, et al. Lycopene supplementation elevates circulating insulin-like growth factor binding protein-1 and -2 concentrations in persons at greater risk of colorectal cancer Am. J. Clinical Nutrition, November 1, 2007; 86(5): 1456 - 1462. [Abstract] [Full Text] [PDF]

				B. Imberti, M. Morigi, S. Tomasoni, C. Rota, D. Corna, L. Longaretti, D. Rottoli, F. Valsecchi, A. Benigni, J. Wang, et al. Insulin-Like Growth Factor-1 Sustains Stem Cell Mediated Renal Repair J. Am. Soc. Nephrol., November 1, 2007; 18(11): 2921 - 2928. [Abstract] [Full Text] [PDF]

				D. Alvaro, G. Macarri, M. G. Mancino, M. Marzioni, M. Bragazzi, P. Onori, S. G. Corradini, P. Invernizzi, A. Franchitto, A. F. Attili, et al. Serum and Biliary Insulin-like Growth Factor I and Vascular Endothelial Growth Factor in Determining the Cause of Obstructive Cholestasis Ann Intern Med, October 2, 2007; 147(7): 451 - 459. [Abstract] [Full Text] [PDF]

				U Berg, T Gustafsson, C J Sundberg, L Kaijser, C Carlsson-Skwirut, and P Bang Interstitial IGF-I in exercising skeletal muscle in women Eur. J. Endocrinol., October 1, 2007; 157(4): 427 - 435. [Abstract] [Full Text] [PDF]

				H. Volzke, N. Friedrich, S. Schipf, R. Haring, J. Ludemann, M. Nauck, M. Dorr, G. Brabant, and H. Wallaschofski Association between Serum Insulin-Like Growth Factor-I Levels and Thyroid Disorders in a Population-Based Study J. Clin. Endocrinol. Metab., October 1, 2007; 92(10): 4039 - 4045. [Abstract] [Full Text] [PDF]

				S.-K. Shields, C. Nicola, and C. Chakraborty Rho Guanosine 5'-Triphosphatases Differentially Regulate Insulin-Like Growth Factor I (IGF-I) Receptor-Dependent and -Independent Actions of IGF-II on Human Trophoblast Migration Endocrinology, October 1, 2007; 148(10): 4906 - 4917. [Abstract] [Full Text] [PDF]

				T. C. Nichols, W. H. Busby Jr., E. Merricks, J. Sipos, M. Rowland, K. Sitko, and D. R. Clemmons Protease-Resistant Insulin-Like Growth Factor (IGF)-Binding Protein-4 Inhibits IGF-I Actions and Neointimal Expansion in a Porcine Model of Neointimal Hyperplasia Endocrinology, October 1, 2007; 148(10): 5002 - 5010. [Abstract] [Full Text] [PDF]

				J. C. Woodworth, M. D. Tokach, J. L. Nelssen, R. D. Goodband, S. S. Dritz, S. I. Koo, J. E. Minton, and K. Q. Owen Influence of dietary L-carnitine and chromium picolinate on blood hormones and metabolites of gestating sows fed one meal per day J Anim Sci, October 1, 2007; 85(10): 2524 - 2537. [Abstract] [Full Text] [PDF]

				J. D. Schertzer, S. M. Gehrig, J. G. Ryall, and G. S. Lynch Modulation of Insulin-like Growth Factor (IGF)-I and IGF-Binding Protein Interactions Enhances Skeletal Muscle Regeneration and Ameliorates the Dystrophic Pathology in mdx Mice Am. J. Pathol., October 1, 2007; 171(4): 1180 - 1188. [Abstract] [Full Text] [PDF]

				H. M. El-Shewy, M.-H. Lee, L. M. Obeid, A. A. Jaffa, and L. M. Luttrell The Insulin-like Growth Factor Type 1 and Insulin-like Growth Factor Type 2/Mannose-6-phosphate Receptors Independently Regulate ERK1/2 Activity in HEK293 Cells J. Biol. Chem., September 7, 2007; 282(36): 26150 - 26157. [Abstract] [Full Text] [PDF]

				F. Xue and K. B Michels Diabetes, metabolic syndrome, and breast cancer: a review of the current evidence Am. J. Clinical Nutrition, September 1, 2007; 86(3): 823S - 835S. [Abstract] [Full Text] [PDF]

				K. E. Govoni, S. K. Lee, Y.-S. Chung, R. R. Behringer, J. E. Wergedal, D. J. Baylink, and S. Mohan Disruption of insulin-like growth factor-I expression in type II{alpha}I collagen-expressing cells reduces bone length and width in mice Physiol Genomics, August 20, 2007; 30(3): 354 - 362. [Abstract] [Full Text] [PDF]

				B. M. Wolpin, D. S. Michaud, E. L. Giovannucci, E. S. Schernhammer, M. J. Stampfer, J. E. Manson, B. B. Cochrane, T. E. Rohan, J. Ma, M. N. Pollak, et al. Circulating Insulin-Like Growth Factor Binding Protein-1 and the Risk of Pancreatic Cancer Cancer Res., August 15, 2007; 67(16): 7923 - 7928. [Abstract] [Full Text] [PDF]

				E. M. N. Bannink, J. van Doorn, P. G. H. Mulder, and A. C. S. Hokken-Koelega Free/Dissociable Insulin-Like Growth Factor (IGF)-I, Not Total IGF-I, Correlates with Growth Response during Growth Hormone Treatment in Children Born Small for Gestational Age J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 2992 - 3000. [Abstract] [Full Text] [PDF]

				M. E. Graham, D. M. Kilby, S. M. Firth, P. J. Robinson, and R. C. Baxter The in Vivo Phosphorylation and Glycosylation of Human Insulin-like Growth Factor-binding Protein-5 Mol. Cell. Proteomics, August 1, 2007; 6(8): 1392 - 1405. [Abstract] [Full Text] [PDF]

				B. C. Nindl, J. A. Alemany, M. D. Kellogg, J. Rood, S. A. Allison, A. J. Young, and S. J. Montain Utility of circulating IGF-I as a biomarker for assessing body composition changes in men during periods of high physical activity superimposed upon energy and sleep restriction J Appl Physiol, July 1, 2007; 103(1): 340 - 346. [Abstract] [Full Text] [PDF]