Physiology of insulin-like growth factor-1
- David R Clemmons, MD
David R Clemmons, MD
- Distinguished Professor of Medicine
- University of North Carolina School of Medicine
Insulin-like growth factor-1 (IGF-1) is a hormone that functions as the major mediator of growth hormone (GH)-stimulated somatic growth, as well as a mediator of GH-independent anabolic responses in many cells and tissues. IGF-1 is a small peptide (molecular weight 7647) that circulates in serum bound to high affinity binding proteins. IGF-1 is an unusual peptide in this regard since it is more than 99 percent protein-bound.
IGF-1 is synthesized by multiple mesenchymal cell types. As a result, there are two major mechanisms of IGF-1 regulation:
●IGF-1 that is synthesized in the liver and secreted into the blood is under the control of GH.
●Autocrine/paracrine IGF-1 synthesized in peripheral tissues, such as bone. Its synthesis is controlled by GH and by factors that are secreted locally by the surrounding cell types. Some of the secreted autocrine/paracrine IGF-1 enters into the systemic circulation. Therefore, understanding the regulation of autocrine/paracrine synthesis of IGF-1 is necessary to interpret changes in serum IGF-1 concentrations.
IGF-1 exerts its effects via activation of the IGF-1 receptor . This receptor is widely distributed, which enables blood-transported IGF-1 to coordinate balanced growth among multiple tissues and organs. In contrast, autocrine/paracrine IGF-1 can stimulate local, unbalanced growth independently of systemic GH. Examples of this type of growth regulation are wound healing and growth of the contralateral kidney after unilateral nephrectomy.To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Werner H, Weinstein D, Bentov I. Similarities and differences between insulin and IGF-I: structures, receptors, and signalling pathways. Arch Physiol Biochem 2008; 114:17.
- Adamo ML, Neuenschwander S, LeRoith D, Roberts CT Jr. Structure, expression, and regulation of the IGF-I gene. Adv Exp Med Biol 1993; 343:1.
- Denley A, Cosgrove LJ, Booker GW, et al. Molecular interactions of the IGF system. Cytokine Growth Factor Rev 2005; 16:421.
- Lee YH, White MF. Insulin receptor substrate proteins and diabetes. Arch Pharm Res 2004; 27:361.
- Baserga R. Customizing the targeting of IGF-1 receptor. Future Oncol 2009; 5:43.
- Janssen JA, Varewijck AJ. IGF-IR Targeted Therapy: Past, Present and Future. Front Endocrinol (Lausanne) 2014; 5:224.
- Brown J, Jones EY, Forbes BE. Keeping IGF-II under control: lessons from the IGF-II-IGF2R crystal structure. Trends Biochem Sci 2009; 34:612.
- Firth SM, Baxter RC. Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev 2002; 23:824.
- Kawai M, Breggia AC, DeMambro VE, et al. The heparin-binding domain of IGFBP-2 has insulin-like growth factor binding-independent biologic activity in the growing skeleton. J Biol Chem 2011; 286:14670.
- Lewitt MS, Hilding A, Brismar K, et al. IGF-binding protein 1 and abdominal obesity in the development of type 2 diabetes in women. Eur J Endocrinol 2010; 163:233.
- Kotronen A, Lewitt M, Hall K, et al. Insulin-like growth factor binding protein 1 as a novel specific marker of hepatic insulin sensitivity. J Clin Endocrinol Metab 2008; 93:4867.
- Yakar S, Liu JL, Stannard B, et al. Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc Natl Acad Sci U S A 1999; 96:7324.
- Juul A. Serum levels of insulin-like growth factor I and its binding proteins in health and disease. Growth Horm IGF Res 2003; 13:113.
- Vestergaard PF, Hansen M, Frystyk J, et al. Serum levels of bioactive IGF1 and physiological markers of ageing in healthy adults. Eur J Endocrinol 2014; 170:229.
- Rotwein P. Large-scale analysis of variation in the insulin-like growth factor family in humans reveals rare disease links and common polymorphisms. J Biol Chem 2017; 292:9252.
- Clemmons DR. Clinical utility of measurements of insulin-like growth factor 1. Nat Clin Pract Endocrinol Metab 2006; 2:436.
- Butler AA, Le Roith D. Control of growth by the somatropic axis: growth hormone and the insulin-like growth factors have related and independent roles. Annu Rev Physiol 2001; 63:141.
- Philippou A, Halapas A, Maridaki M, Koutsilieris M. Type I insulin-like growth factor receptor signaling in skeletal muscle regeneration and hypertrophy. J Musculoskelet Neuronal Interact 2007; 7:208.
- Behringer RR, Lewin TM, Quaife CJ, et al. Expression of insulin-like growth factor I stimulates normal somatic growth in growth hormone-deficient transgenic mice. Endocrinology 1990; 127:1033.
- Lupu F, Terwilliger JD, Lee K, et al. Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth. Dev Biol 2001; 229:141.
- Stratikopoulos E, Szabolcs M, Dragatsis I, et al. The hormonal action of IGF1 in postnatal mouse growth. Proc Natl Acad Sci U S A 2008; 105:19378.
- Elis S, Courtland HW, Wu Y, et al. Elevated serum levels of IGF-1 are sufficient to establish normal body size and skeletal properties even in the absence of tissue IGF-1. J Bone Miner Res 2010; 25:1257.
- Yakar S, Setser J, Zhao H, et al. Inhibition of growth hormone action improves insulin sensitivity in liver IGF-1-deficient mice. J Clin Invest 2004; 113:96.
- Kupfer SR, Underwood LE, Baxter RC, Clemmons DR. Enhancement of the anabolic effects of growth hormone and insulin-like growth factor I by use of both agents simultaneously. J Clin Invest 1993; 91:391.
- Clemmons DR. Metabolic actions of insulin-like growth factor-I in normal physiology and diabetes. Endocrinol Metab Clin North Am 2012; 41:425.
- Rajpathak SN, Gunter MJ, Wylie-Rosett J, et al. The role of insulin-like growth factor-I and its binding proteins in glucose homeostasis and type 2 diabetes. Diabetes Metab Res Rev 2009; 25:3.
- Kurmasheva RT, Houghton PJ. IGF-I mediated survival pathways in normal and malignant cells. Biochim Biophys Acta 2006; 1766:1.
- Gardner S, Gross SM, David LL, et al. Separating myoblast differentiation from muscle cell fusion using IGF-I and the p38 MAP kinase inhibitor SB202190. Am J Physiol Cell Physiol 2015; 309:C491.
- Xi G, Wai C, DeMambro V, et al. IGFBP-2 directly stimulates osteoblast differentiation. J Bone Miner Res 2014; 29:2427.
- Clemmons D, Maile L, Xi G, et al. Igf-I signaling in response to hyperglycemia and the development of diabetic complications. Curr Diabetes Rev 2011; 7:235.
- IGF GENES AND STRUCTURE
- IGF-1 RECEPTORS
- IGF-1 receptor
- - Receptor activation
- IGF-2/mannose 6 phosphate receptor
- IGF-BINDING PROTEINS
- Structural differences
- Regulation of plasma IGFBPs
- - IGFBP-3
- - IGFBP-2
- - IGFBP-1
- - IGFBP-4 and -5
- REGULATION OF CIRCULATING IGF-1
- Growth hormone
- Nutritional status
- Other hormones
- REGULATION OF TISSUE IGF-1
- MAJOR PHYSIOLOGIC EFFECTS OF IGF-1
- Whole animal studies
- Transgenic animal models
- Effects of IGF-1 administration to humans
- MECHANISMS OF ACTION OF IGF-1