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Insulin-Like Growth Factors I and II. Peptide, Messenger Ribonucleic Acid and Gene Structures, Serum, and Tissue Concentrations^*

Metabolism Division, Department of Medicine, Washington University School of Medicine Saint Louis, Missouri, 63110
Department of Genetics, Washington University School of Medicine Saint Louis, Missouri, 63110

Abstract

Introduction: HYPOPHYSECTOMIZED rats have a defect in the synthesis of matrix protein which is rapidly repaired by the administration of GH in vivo. In 1957, it was first reported that this defect, as determined by measuring the incorporation of [³⁵S]sulfate into chondroitin sulfate, could not be corrected by addition of GH to media containing cartilage segments (1). The defect, however, was rapidly corrected by the addition of diluted normal rat serum to such media, but serum from hypophysectomized rats was virtually inactive. It was proposed that GH acted on skeletal tissues by inducing the formation of a direct acting intermediary growth factor. This hypothesis, commonly referred to as the somatomedin hypothesis, has been extensively confirmed and recently extended to include autocrine and paracrine roles of somatomedins in many tissues as well as the originally recognized endocrine role of this growth factor.

Research in the somatomedins has increased so much in recent years that a comprehensive review of the subject is no longer possible within the length constraints of this Journal. In this review, we will focus on the insulin-like growth factors (IGFs) that are present in body fluids and tissues. We will review the rapidly developing information about the molecular biology of the biosynthesis of IGFs and their regulation in fetal and postnatal life and the possible role of IGF biosynthesis in tissue repair and hypertrophy. Last, we will consider the relative contribution of endocrine as opposed to autocrine/paracrine actions of IGF-I in skeletal growth. Not included in this review will be a consideration of IGF binding proteins, IGF receptors, and postbinding effector mechanisms. Readers are referred to recent reviews for consideration of these topics (2–4).

Footnotes

^* This work was supported by NIH Grant HD-20805.

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				P. Kermer, N. Klocker, M. Labes, and M. Bahr Insulin-Like Growth Factor-I Protects Axotomized Rat Retinal Ganglion Cells from Secondary Death via PI3-K-Dependent Akt Phosphorylation and Inhibition of Caspase-3 In Vivo J. Neurosci., January 15, 2000; 20(2): 722 - 728. [Abstract] [Full Text] [PDF]

				A. Nguyen and J. Pollard Transforming growth factor beta3 induces cell death during the first stage of mammary gland involution Development, January 7, 2000; 127(14): 3107 - 3118. [Abstract] [PDF]

				V. Hwa, Y. Oh, and R. G. Rosenfeld The Insulin-Like Growth Factor-Binding Protein (IGFBP) Superfamily Endocr. Rev., December 1, 1999; 20(6): 761 - 787. [Abstract] [Full Text]

				D. LeRoith Insulin-like Growth Factors in Pediatric Health and Disease J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4355 - 4361. [Full Text]

				Measures of Submaximal Aerobic Performance Evaluate and Predict Functional Response to Growth Hormone (GH) Treatment in GH-Deficient Adults J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4570 - 4577. [Abstract] [Full Text]

				F. Gori, L. C. Hofbauer, C. A. Conover, and S. Khosla Effects of Androgens on the Insulin-Like Growth Factor System in an Androgen-Responsive Human Osteoblastic Cell Line Endocrinology, December 1, 1999; 140(12): 5579 - 5586. [Abstract] [Full Text]

				B. T. Ameredes, J. F. Watchko, M. J. Daood, J. F. Rosas, M. P. Donahoe, and R. M. Rogers Growth Hormone Improves Body Mass Recovery with Refeeding after Chronic Undernutrition-Induced Muscle Atrophy in Aging Male Rats J. Nutr., December 1, 1999; 129(12): 2264 - 2270. [Abstract] [Full Text]

				D. M. Sutkowski, R. L. Goode, J. Baniel, C. Teater, P. Cohen, A. M. McNulty, H. M. Hsiung, G. W. Becker, and B. L. Neubauer Growth Regulation of Prostatic Stromal Cells by Prostate-Specific Antigen J Natl Cancer Inst, October 6, 1999; 91(19): 1663 - 1669. [Abstract] [Full Text] [PDF]

				B. T. Ameredes, J. F. Watchko, M. J. Daood, J. F. Rosas, M. P. Donahoe, and R. M. Rogers Growth hormone restores aged diaphragm myosin composition and performance after chronic undernutrition J Appl Physiol, October 1, 1999; 87(4): 1253 - 1259. [Abstract] [Full Text] [PDF]

				J.-L. Zhu, C.-I Pao, E. Hunter Jr., K.-w. M. Lin, G.-j. Wu, and L. S. Phillips Identification of Core Sequences Involved in Metabolism-Dependent Nuclear Protein Binding to the Rat Insulin-Like Growth Factor I Gene Endocrinology, October 1, 1999; 140(10): 4761 - 4771. [Abstract] [Full Text]

				K. Thorsen, P. Nordström, R. Lorentzon, and G. H. Dahlén The Relation between Bone Mineral Density, Insulin-Like Growth Factor I, Lipoprotein (a), Body Composition, and Muscle Strength in Adolescent Males J. Clin. Endocrinol. Metab., September 1, 1999; 84(9): 3025 - 3029. [Abstract] [Full Text]

				L. Stefaneanu, L. Powell-Braxton, W. Won, V. Chandrashekar, and A. Bartke Somatotroph and Lactotroph Changes in the Adenohypophyses of Mice with Disrupted Insulin-Like Growth Factor I Gene Endocrinology, September 1, 1999; 140(9): 3881 - 3889. [Abstract] [Full Text]

				D. Deplewski and R. L. Rosenfield Growth Hormone and Insulin-Like Growth Factors Have Different Effects on Sebaceous Cell Growth and Differentiation Endocrinology, September 1, 1999; 140(9): 4089 - 4094. [Abstract] [Full Text]

				D. C. Martin, J. L. Fowlkes, B. Babic, and R. Khokha Insulin-like Growth Factor II Signaling in Neoplastic Proliferation Is Blocked by Transgenic Expression of the Metalloproteinase Inhibitor Timp-1 J. Cell Biol., August 23, 1999; 146(4): 881 - 892. [Abstract] [Full Text] [PDF]

				L. Poretsky, N. A. Cataldo, Z. Rosenwaks, and L. C. Giudice The Insulin-Related Ovarian Regulatory System in Health and Disease Endocr. Rev., August 1, 1999; 20(4): 535 - 582. [Abstract] [Full Text] [PDF]

				T. Gustafsson, P. Andersson, Y. Chen, J. O. Magnusson, and H. J. Arnqvist Interaction of angiotensin II and the insulin-like growth factor system in vascular smooth muscle cells Am J Physiol Heart Circ Physiol, August 1, 1999; 277(2): H499 - H507. [Abstract] [Full Text] [PDF]

				S. Yakar, J.-L. Liu, B. Stannard, A. Butler, D. Accili, B. Sauer, and D. LeRoith Normal growth and development in the absence of hepatic insulin-like growth factor I PNAS, June 22, 1999; 96(13): 7324 - 7329. [Abstract] [Full Text] [PDF]

				K. Sjogren, J.-L. Liu, K. Blad, S. Skrtic, O. Vidal, V. Wallenius, D. LeRoith, J. Tornell, O. G. P. Isaksson, J.-O. Jansson, et al. Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice PNAS, June 8, 1999; 96(12): 7088 - 7092. [Abstract] [Full Text] [PDF]

				Z.-D. Xu, L. Oey, S. Mohan, M. H. Kawachi, N.-S. Lee, J. J. Rossi, and Y. Fujita-Yamaguchi Hammerhead Ribozyme-Mediated Cleavage of the Human Insulin-Like Growth Factor-II Ribonucleic Acid in Vitro and in Prostate Cancer Cells Endocrinology, May 1, 1999; 140(5): 2134 - 2144. [Abstract] [Full Text]

				K. M. Kelley, T. R. Johnson, J. Ilan, and R. W. Moskowitz Glucose regulation of the IGF response system in chondrocytes: induction of an IGF-I-resistant state Am J Physiol Regulatory Integrative Comp Physiol, April 1, 1999; 276(4): R1164 - R1171. [Abstract] [Full Text] [PDF]

				J. B. Lawrence, C. Oxvig, M. T. Overgaard, L. Sottrup-Jensen, G. J. Gleich, L. G. Hays, J. R. Yates III, and C. A. Conover The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A PNAS, March 16, 1999; 96(6): 3149 - 3153. [Abstract] [Full Text] [PDF]

				D. R. Powell, S. K. Durham, E. D. Brewer, J. W. Frane, S. L. Watkins, R. J. Hogg, and S. Mohan Effects of Chronic Renal Failure and Growth Hormone on Serum Levels of Insulin-Like Growth Factor-Binding Protein-4 (IGFBP-4) and IGFBP-5 in Children: A Report of the Southwest Pediatric Nephrology Study Group J. Clin. Endocrinol. Metab., February 1, 1999; 84(2): 596 - 601. [Abstract] [Full Text]

				N. Kawai, S. Kanzaki, S. Takano-Watou, C. Tada, Y. Yamanaka, T. Miyata, M. Oka, and Y. Seino Serum Free Insulin-Like Growth Factor I (IGF-I), Total IGF-I, and IGF-Binding Protein-3 Concentrations in Normal Children and Children with Growth Hormone Deficiency J. Clin. Endocrinol. Metab., January 1, 1999; 84(1): 82 - 89. [Abstract] [Full Text]

				L. E. Underwood Special Considerations in the Design of Trials Involving Children J. Nutr., January 1, 1999; 129(1): 264S - 264S. [Full Text] [PDF]