insulin-like growth factors (IGFs)

see also:

• endocrinology
• insulin
• growth hormone / somatotropin

• insulin-like peptides are ancient peptides which evolved in metazoans long before vertebrate evolution, however, the basal vertebrate tetrapoidization events of chromosomal duplication resulted in increased diversification of these peptides and the ancestral insulin-like gene diverged into insulin, IGF-1 and IGF-2, and several ILPs including relaxin and relaxin-like peptide.
• IGFs have a variety of roles as endocrine, paracrine and autocrine factors that promote cell growth, proliferation, differentiation, survival, wound healing, development of CNS and other tissues, regulation of protein, carbohydrate, and lipid metabolism, neuroprotection, and aging
• both IGF-1 and IGF-2 bind to the IGF-1 receptor (IGF1R), which is expressed in almost all cells, with hepatocytes being an important exception in mammals
• IGFs are sufficiently structurally similar to insulin that they can cross react with the insulin receptor (IR)
• the diverse functions of this central hormonal pathway require that robust regulatory mechanisms be in place to avoid inappropriate regulation and/or dysfunction in different tissues and at different times ¹⁾
• IGF signalling is regulated by a family of specific IGF-binding proteins (IGFBPs) of which there are six distinct types in vertebrates and which have a greater affinity to bind to IGFs than does the IGF receptor, and normally, most IGF in circulation and in local tissues is actually bound to IGFBPs blocking their ability to bind the IGF-1 receptor and also to the insulin receptor which would otherwise result in hypoglycaemic effects, but also extending their half life in circulation from 10 minutes to around 25 minutes, but if it forms a ternary complex with ALS which prevents its diffusion across capillaries, the half life is extended to 16hrs.
  • deletion of the ALS gene in mice results in 60% reduction in circulating IGFs and 15-20% reduction in post-natal growth
• some IGFBPs can “deliver” IGFs to specific target tissues via their other binding sites and thereby enhance their actions
  • eg. IGFBP-5 increases IGF-2 levels at myoblasts in myogenesis but pathologically, also has a role in the progression of atherosclerosis perhaps via its local upregulation
• Several proteases are known to cleave IGFBPs, and the resulting proteolytic fragments have greatly reduced binding affinity for IGFs. This leads to the liberation of IGFs from the IGF/IGFBP complex and increases the amount of IGFs available for IGF1R binding, thereby converting the inhibition of IGF signaling into an enhancement, examples include:
  • specific IGFBP proteases such as proteases pregnancy-associated plasma protein A (PAPP-A) and PAPP-A2 act on IGFBP-4

• this is the main IGF in adult humans with highest levels during the pubertal growth spurt
• also called somatomedin C, and the gene in humans is located on chromosome 12q23.2
• secreted by the liver into the circulation in response to growth hormone stimulation
• secreted by local tissues in response to growth hormone stimulation
• thus IGF-1 is a primary mediator of the actions of growth hormone both globally and locally
• IGF-1 is one of the most potent natural activators of the AKT signaling pathway, a stimulator of cell growth and proliferation, and a potent inhibitor of programmed cell death
• knockout of IGF-1 in mice results in a 60% reduction in prenatal growth followed by perinatal lethality for over 95% of mutant pups
• IGF-1 signaling is an important mitogenic and morphogenetic regulator in hair follicle biology and IGF-1 tissue regulation in hair follicles is modified by androgens
• hyperinsulinemia increases the serum level of free IGF–1 and decreases the serum level of insulin-like growth factor binding protein (IGFBP)–3
  • hyperinsulinemia and increased IGF-1 levels directly result in the growth of epithelial and fibroblastic cells via receptor activation.
  • this association explains the relatively frequent development of acrochordon (skin tags) and pseudoacanthosis nigricans in hyperinsulinemic patients
  • it appears that increased expression of IGF-1 and IGF-2 receptors may be causal factors in development of acrochordon (skin tags) regardless of impairment in glucose metabolism ²⁾
  • increased expression of IGF-1 and IGF-2 receptors appear to be due to:
    • high HOMA-IR (insulin resistance)
    • increased levels of IGF-1
    • hyperinsulinaemia
    • high BMI
    • increase in IGF–2R levels may be due to negative feedback secondary to the increase of IGF–1
  • acrochordons are associated with high fasting insulin levels rather than high fasting glucose levels
  • a high number of acrochordons (> 8) may be a cutaneous manifestation of hyperinsulinemia and pre-diabetic status
  • obesity, multiple acrochordons, abnormal glucose tolerance, pseudoacanthosis nigricans, and seborrheic keratoses may be components of a syndrome

• Laron dwarfism
  • Severe primary IGF deficiency includes patients with mutations in the GH receptor, post-receptor mutations or IGF mutations and thus they fail to respond to exogenous somatostatin
  • these patients have short stature, sparse hair, prominent forehead, depressed nasal bridge, underdevelopment of the mandible, and truncal obesity

• in humans, the IGF2 gene is located on chromosome 11p15.5 but subject to imprinting and thus only the paternal allele is active except in some regions of the brain
• it exerts its effects by binding to IGF-1 receptor but may also bind to the IGF-2 receptor (also called the cation-independent mannose 6-phosphate receptor), which acts as a signalling antagonist and prevents IGF2 responses
  • IGF-2R is thought to suppress tumor growth and proliferation by indirectly suppressing IGF-1R activation
• it is the major fetal growth factor
• it has a key role as a co-hormone during the menstrual cycle:
  • IGF2 with FSH promotes granulosa cell proliferation during the follicular phase of the menstrual cycle
  • after ovulation, IGF-2 and LH promotes progesterone secretion during the luteal phase of the menstrual cycle
• it may have a role in memory
• during myogenesis, IGF-2 is produced locally at high levels and this is required for myoblast differentiation

• this may occur due to:
  • islet cell tumours
  • non-islet hypoglycaemic cell tumors
  • several tumours like uterine leiomyosarcoma, ovarian cancer, endometrial cancer, cervical cancer, breast carcinoma, and testicular tumors have been shown to over secrete IGF-2
  • Doege-Potter syndrome
    • a paraneoplastic syndrome
    • hypoglycemia is associated with the presence of one or more non-islet fibrous tumors in the pleural cavity
  • loss of genomic imprinting
    • Beckwith-Wiedemann syndrome and its associated risk of childhood cancers
    • this occurs in normal colonic mucosa in 10% of healthy individuals but in 30% of those with colorectal cancer (bowel cancer) and thus its presence in lymphocytes was found to give an odds ratio of 21.7 for colorectal cancer (bowel cancer) ³⁾
    • maternal pre-eclampsia where it may cause increased risk of metabolic diseases later in life for the child
• clinical features
  • usually hypoglycaemia

• possible causative role in polycystic ovary syndrome (PCOS) / polyendocrine metabolic ovarian syndrome (PMOS)
  • the A820G ApaI polymorphism in the IGF2 gene appears to confer significant risk for polycystic ovary syndrome (PCOS) / polyendocrine metabolic ovarian syndrome (PMOS) (G genotype has 7.6x risk of PCOS, GG genotype had 19.6x risk)⁴⁾

• the IGFBP family is evolutionarily ancient with the 6 types probably evolving as a result of the basal vertebrate tetrapoidization events of chromosomal duplication and highly conserved in vertebrates
• many of the functions of different IGFBPs are made possible by their unique collection of functional motifs such as binding sites for heparin, cell surface proteoglycans, etc
• IGFBP-2, -3, -5, and -6 all contain functional nuclear localization sequences by which they are imported into the cell nucleus in certain cell types
• IGFBP-3 is the most prevalent in adult serum with a concentration of around 100 nM/L and is secreted by the liver in response to growth hormone stimulation so that levels match that of IGFs
• IGFBP-1 is synthesized in the liver and its expression and secretion is highly induced by starvation, hypoxia, stress, and corticosteroids and reduced by insulin.
  • IGFBP-1 has a role in reducing the rate of development and growth by binding to IGFs and inhibiting IGF activity
• in vascular smooth muscle cells, IGFBP-4 acts to block IGF-1 from interacting with the IGF1R and thereby inhibits IGF-1-stimulated DNA synthesis and may be involved in inhibiting atherosclerosis
• some IGFBPs have been reported to have cellular actions that are independent of their IGF binding
  • the integrin-binding RGD motif found in IGFBPs 1 and 2 allows them to promote cell migration and influence cell adhesion, respectively
  • IGFBP-5 and -3 possess functional nuclear localization sequences and can enter the nucleus
  • paracrine IGFBP-4 was shown to promote differentiation of cardiomyocytes by inhibiting Wnt signaling in an IGF-independent manner
• knockout studies
  • apparently minimal adverse effects if only one IGFBP knocked out in mice
  • triple knockout of IGFBP-3, -4, in mice, results in a 25% reduction in body growth, decreased fat accumulation and quadriceps muscle mass, expanded pancreatic islets, and enhanced glucose homeostasis