J Clin Pathol: Mol Pathol 2001;54:311–316 311 Insulin-like growth factor 1 (IGF-1): a growth hormone Mol Path: first published as 10.1136/mp.54.5.311 on 1 October 2001. Downloaded from Z Laron Abstract independent growth stimulating eVect, Aim—To contribute to the debate about which with respect to cartilage cells is whether growth hormone (GH) and possibly optimised by the synergistic ac- insulin-like growth factor 1 (IGF-1) act tion with GH. independently on the growth process. (J Clin Pathol: Mol Pathol 2001;54:311–316) Methods—To describe growth in human and animal models of isolated IGF-1 defi- Keywords: insulin-like growth factor I; growth hor- ciency (IGHD), such as in Laron syn- mones; Laron syndrome; growth drome (LS; primary IGF-1 deficiency and GH resistance) and IGF-1 gene or GH In recent years, new technologies have enabled receptor gene knockout (KO) mice. many advances in the so called growth Results—Since the description of LS in hormone (GH) axis (fig 1). Thus, it has been 1966, 51 patients were followed, many found that GH secretion from the anterior since infancy. Newborns with LS are pituitary is regulated not only by GH releasing shorter (42–47 cm) than healthy babies hormone (GHRH) and somatostatin (GH (49–52 cm), suggesting that IGF-1 has secretion inhibiting hormone),1 but also by some influence on intrauterine growth. other hypothalamic peptides called GH secre- Newborn mice with IGF-1 gene KO are tagogues,2 which seem to act in synergism with 30% smaller. The postnatal growth rate of GHRH3 by inhibiting somatostatin.4 One of patients with LS is very slow, the distance these has been cloned and named Ghrelin.5 from the lowest normal centile increasing The interplay between GHRH and somatosta- progressively. If untreated, the final height tin induces a pulsatile GH secretion,6 which is Endocrinology and is 100–136 cm for female and 109–138 cm highest during puberty. GH induces the Diabetes Research for male patients. They have acromicia, Unit, WHO generation of insulin-like growth factor 1 organomicria including the brain, heart, (IGF-1, also called somatomedin 1) in the liver Collaborating Center gonads, genitalia, and retardation of skel- for the Study of and regulates the paracrine production of Diabetes in Youth, etal maturation. The availability of bio- IGF-1 in many other tissues.7 Schneider Children’s synthetic IGF-1 since 1988 has enabled it http://mp.bmj.com/ Medical Center, Tel to be administered to children with LS. It Aviv University, 14 accelerated linear growth rates to 8–9 cm IGF-1 Kaplan Street, Petah in the first year of treatment, compared IGF-1 and IGF-2 were identified in 1957 by Tikva 49202, Tel Aviv, Salmon and Daughaday8 and designated “sul- Israel with 10–12 cm/year during GH treatment Z Laron of IGHD. The growth rate in following phation factor” by their ability to stimulate years was 5–6.5 cm/year. 35-sulphate incorporation into rat cartilage. Correspondence to: Conclusion—IGF-1 is an important Froesch et al described the non-suppressible Professor Laron growth hormone, mediating the protein insulin-like activity (NSILA) of two soluble on September 28, 2021 by guest. Protected copyright. [email protected] anabolic and linear growth promoting serum components (NSILA I and II).9 In Accepted 24 April 2001 eVect of pituitary GH. It has a GH 1972, the labels sulphation factor and NSILA were replaced by the term “somatomedin”, (CNS) denoting a substance under control and medi- Neurotransmitters ating the eVects of GH.10 In 1976, Rinderk- + (hypothalamus) + 11 – – necht and Humbel isolated two active sub- stances from human serum, which owing to + – their structural resemblance to proinsulin were GHRHGH-S Somatostatin renamed “insulin-like growth factor 1 and 2” (pituitary) – Sex (IGF-1 and 2). IGF-1 is the mediator of the + – 12 GH steroids anabolic and mitogenic activity of GH. + – GHBP + (pancreas) – CHEMICAL STRUCTURE + + Insulin + The IGFs are members of a family of insulin – (liver) IGF-1 – related peptides that include relaxin and – + several peptides isolated from lower inverte- brates.13 IGF-1 is a small peptide consisting of IGFBP-3; IGFBP-2; IGFBP-1 70 amino acids with a molecular weight of 7649 Da.14 Similar to insulin, IGF-1 has an A and B chain connected by disulphide bonds. Target tissues The C peptide region has 12 amino acids. The structural similarity to insulin explains the Figure 1 The cascade of the growth hormone axis. CNS, central nervous system; GH, growth hormone; GHBP,GH binding protein; GH-S, GH secretagogues; IGF-1, ability of IGF-1 to bind (with low aYnity) to insulin-like growth factor 1; IGFBPs, IGF binding proteins; +, stimulation; –, inhibition. the insulin receptor. www.molpath.com 312 Laron α Subunit β Subunit á subunits and transmembrane â subunits. The á subunits have binding sites for IGF-1 and are Mol Path: first published as 10.1136/mp.54.5.311 on 1 October 2001. Downloaded from linked by disulphide bonds (fig 3). The â subu- 1 2 3 4 5 6 7 8 910 11121314151617 18 19 20 21 nit has a short extracellular domain, a trans- Gene membrane domain, and an intracellular do- main. The intracellular part contains a tyrosine Transcription kinase domain, which constitutes the signal transduction mechanism. Similar to the insulin receptor, the IGF-1 receptor undergoes ligand induced autophosphorylation.25 The activated mRNA IGF-1 receptor is capable of phosphorylating mRNA other tyrosine containing substrates, such as insulin receptor substrate 1 (IRS-1), and INR AUG continues a cascade of enzyme activations via Figure 2 Type 1 insulin-like growth factor receptor gene and mRNA. Reproduced with phosphatidylinositol-3 kinase (PI3-kinase), permission from Werner.22 Grb2 (growth factor receptor bound protein THE IGF-1 GENE 2), Syp (a phophotyrosine phosphatase), Nck The IGF-1 gene is on the long arm of chromo- (an oncogenic protein), and Shc (src homology some 12q23–23.15 16 The human IGF-1 gene domain protein), which associated to Grb2, consists of six exons, including two leader activates Raf, leading to a cascade of protein exons, and has two promoters.17 kinases including Raf, mitogen activated pro- tein (MAP) kinase, 5 G kinase, and others.26 IGF binding proteins (IGFBPs) In the plasma, 99% of IGFs are complexed to Physiology a family of binding proteins, which modulate IGF-1 is secreted by many tissues and the the availability of free IGF-1 to the tissues. secretory site seems to determine its actions. There are six binding proteins.18 In humans, Most IGF-1 is secreted by the liver and is almost 80% of circulating IGF-1 is carried by transported to other tissues, acting as an endo- crine hormone.27 IGF-1 is also secreted by IGFBP-3, a ternary complex consisting of one 28 molecule of IGF-1, one molecule of IGFBP-3, other tissues, including cartilagenous cells, and acts locally as a paracrine hormone (fig and one molecule of an 88 kDa protein named 29 19 4). It is also assumed that IGF-1 can act in an acid labile subunit. IGFBP-1 is regulated by 30 insulin and IGF-120; IGFBP-3 is regulated autocrine manner as an oncogene. The role of mainly by GH but also to some degree by IGF-1 in the metabolism of many tissues IGF-1.21 including growth has been reviewed re- cently.31 32 The IGF-1 receptor The following is an analysis of whether The human IGF-1 receptor (type 1 receptor) is IGF-1, the anabolic eVector hormone of pitui- http://mp.bmj.com/ the product of a single copy gene spanning over tary GH, is the “real growth hormone”. 100 kb of genomic DNA at the end of the long arm of chromosome 15q25–26.22 The gene Is IGF-1 “a” or “the” growth hormone? contains 21 exons (fig 2) and its organisation The discussion on the role of IGF-1 in body resembles that of the structurally related insu- growth will be based on growth in states of lin receptor (fig 3).23 The type 1 IGF receptor IGF-1 deficiency and the eVects of exogenous IGF-1 administration. Experiments in nature gene is expressed by almost all tissues and cell on September 28, 2021 by guest. Protected copyright. types during embryogenesis.24 In the liver, the (gene deletion or gene mutations) or experi- organ with the highest IGF-1 ligand expres- mental models in animals, such as gene knock- outs, help us in this endeavour. In 1966 and sion, IGF-1 receptor mRNA is almost undetec- 33 34 table, possibly because of the “downregula- 1968, we described a new type of dwarfism tion” of the receptor by the local production of indistinguishable from genetic isolated GH IGF-1. The type 1 IGF receptor is a heterote- deficiency (IGHD), but characterised by high tramer composed of two extracellular spanning serum GH values. Subsequent studies revealed that these patients cannot generate IGF-1.35 Insulin receptor IGF-1 receptor This syndrome of GH resistance (insensitiv- ity) was named by Elders et al as Laron dwarf- ism,36 a name subsequently changed to Laron 37 Cysteine rich syndrome (LS). Molecular studies revealed 38 domains that the causes of GH resistance are deletions or mutations39 in the GH receptor gene, result- α Subunits ing in the failure to generate IGF-1 and a reduction in the synthesis of several other sub- stances, including IGFBP-3. This unique model in humans has enabled the study of the Tyrosine kinase diVerential eVects of GH and IGF-1.