Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a protein that in humans is encoded by the IGF1gene. IGF-1 has also been referred to as a "sulfation factor" and its effects were termed "nonsuppressible insulin-like activity" (NSILA) in the 1970s.
IGF-1 is produced primarily by the liver as an endocrine hormone as well as in target tissues in a paracrine/autocrine fashion. Production is stimulated by growth hormone (GH) and can be retarded by undernutrition, growth hormone insensitivity, lack of growth hormone receptors, or failures of the downstream signalling pathway post GH receptor including SHP2 and STAT5B. Approximately 98% of IGF-1 is always bound to one of 6 binding proteins (IGF-BP). IGFBP-3, the most abundant protein, accounts for 80% of all IGF binding. IGF-1 binds to IGFBP-3 in a 1:1 molar ratio.
In rat experiments the amount of IGF-1 mRNA in the liver was positively associated with dietary casein and negatively associated with a protein-free diet.
Recently, an efficient plant expression system was developed to produce biologically active recombinant human IGF-I (rhIGF-I) in transgenic rice grains.
Deficiency of either growth hormone or IGF-1 therefore results in diminished stature. GH-deficient children are given recombinant GH to increase their size. IGF-1 deficient humans, who are categorized as having Laron syndrome, or Laron's dwarfism, are treated with recombinant IGF-1. In beef cattle, circulating IGF-1 concentrations are related to reproductive performance.
Insulin-like growth factor 1 receptor (IGF-1R) and other tyrosine kinase growth factor receptors signal through multiple pathways. A key pathway is regulated by phosphatidylinositol-3 kinase (PI3K) and its downstream partner, the mammalian target of rapamycin (mTOR). Rapamycins complex with FKBPP12 to inhibit the mTORC1 complex. mTORC2 remains unaffected and responds by upregulating Akt, driving signals through the inhibited mTORC1. Phosphorylation of eukaryotic initiation factor 4e (eif-4E) [4EBP] by mTOR inhibits the capacity of 4EBP to inhibit eif-4E and slow metabolism.
IGF-1 binds to at least two cell surface receptors: the IGF-1 receptor (IGF1R), and the insulin receptor. The IGF-1 receptor seems to be the "physiologic" receptor - it binds IGF-1 at significantly higher affinity than the IGF-1 that is bound to the insulin receptor. Like the insulin receptor, the IGF-1 receptor is a receptor tyrosine kinase - meaning it signals by causing the addition of a phosphate molecule on particular tyrosines. IGF-1 activates the insulin receptor at approximately 0.1x the potency of insulin. Part of this signaling may be via IGF1R/Insulin Receptor heterodimers (the reason for the confusion is that binding studies show that IGF1 binds the insulin receptor 100-fold less well than insulin, yet that does not correlate with the actual potency of IGF1 in vivo at inducing phosphorylation of the insulin receptor, and hypoglycemia).
IGF-1 is produced throughout life. The highest rates of IGF-1 production occur during the pubertal growth spurt. The lowest levels occur in infancy and old age.
Other IGFBPs are inhibitory. For example, both IGFBP-2 and IGFBP-5 bind IGF-1 at a higher affinity than it binds its receptor. Therefore, increases in serum levels of these two IGFBPs result in a decrease in IGF-1 activity.
Related growth factors
IGF-1 is closely related to a second protein called "IGF-2". IGF-2 also binds the IGF-1 receptor. However, IGF-2 alone binds a receptor called the "IGF-2 receptor" (also called the mannose-6 phosphate receptor). The insulin-like growth factor-II receptor (IGF2R) lacks signal transduction capacity, and its main role is to act as a sink for IGF-2 and make less IGF-2 available for binding with IGF-1R. As the name "insulin-like growth factor 1" implies, IGF-1 is structurally related to insulin, and is even capable of binding the insulin receptor, albeit at lower affinity than insulin.
A splice variant of IGF-1 sharing an identical mature region, but with a different E domain is known as mechano-growth factor (MGF).
Factors influencing the levels in the circulation
3-d model of IGF-1
Factors that are known to cause variation in the levels of growth hormone (GH) and IGF-1 in the circulation include: genetic make-up, the time of day, age, sex, exercise status, stress levels, nutrition level and body mass index (BMI), disease state, race, estrogen status and xenobiotic intake. The later inclusion of xenobiotic intake as a factor influencing GH-IGF status highlights the fact that the GH-IGF axis is a potential target for certain endocrine disrupting chemicals - see also endocrine disruptor. In free-ranging animals, nutrition and predators may influences levels of IGF-1.
It is now widely accepted that signaling through the insulin/IGF-1-like receptor pathway is a significant contributor to the biological aging process in many organisms. This avenue of research first achieved prominence with the work of Cynthia Kenyon, who showed that mutations in the daf-2gene double the lifespan of the roundworm, C. elegans. Daf-2 encodes the worm's unified insulin/IGF-1-like receptor. Despite the impact of IGF1-like on C. elegans longevity, direct application to mammalian aging is not as clear as mammals do not form dauer-like developmental stages.
Insulin/IGF-1-like signaling is conserved from worms to humans. In vitro experiments show that mutations that reduce insulin/IGF-1 signaling have been shown to decelerate the degenerative aging process and extend lifespan in a wide range of organisms, including Drosophila melanogaster, mice, and possibly humans. Reduced IGF-1 signaling is also thought to contribute to the "anti-aging" effects of Calorie restriction.
Nevertheless the situation in vivo is evidently different. Anabolic deficiency in men with chronic heart failure is prevalent and could have an associated detrimental impact on survival. Deficiency of anabolic hormones identifies groups with a higher mortality.
Therapeutic administration with neurotrophic proteins (IGF I) is associated with potential reversal of degeneration of spinal cord motor neuron axons in certain peripheral neuropathies.
Rare diseases characterized by inability to make or respond to IGF-1 produce a distinctive type of growth failure. One such disorder, termed Laron dwarfism does not respond at all to growth hormone treatment due to a lack of GH receptors. The FDA has grouped these diseases into a disorder called severe primary IGF deficiency. Patients with severe primary IGFD typically present with normal to high GH levels, height below -3 standard deviations (SD), and IGF-1 levels below -3SD. Severe primary IGFD includes patients with mutations in the GH receptor, post-receptor mutations or IGF mutations, as previously described. As a result, these patients cannot be expected to respond to GH treatment.
People with Laron syndrome have strikingly low rates of cancer and diabetes.
The IGF signaling pathway has a pathogenic role in cancer. Studies have shown that decreased levels of IGF lead to decreased growth of existing cancer cells. People with Laron syndrome have also recently been shown to be of much less risk to develop cancer.
Interpretation of IGF-1 levels is complicated by the wide normal ranges, and marked variations by age, sex, and pubertal stage. Clinically significant conditions and changes may be masked by the wide normal ranges. Sequential management over time is often useful for the management of several types of pituitary disease, undernutrition, and growth problems.
As a therapeutic agent
Mecasermin (brand name Increlex) is a synthetic analog of IGF-1 which is approved for the treatment of growth failure. IGF-1 has been manufactured recombinantly on a large scale using both yeast and E. coli.
Several companies have evaluated IGF-1 in clinical trials for a variety of additional indications, including type 1 diabetes, type 2 diabetes, amyotrophic lateral sclerosis (ALS aka "Lou Gehrig's Disease"), severe burn injury and myotonic muscular dystrophy (MMD). Results of clinical trials evaluating the efficacy of IGF-1 in type 1 diabetes and type 2 diabetes showed great promise in reducing hemoglobin A1C levels, as well as daily insulin consumption. However, the sponsor, Genentech, discontinued the program due to an exacerbation of diabetic retinopathy in patients coupled with a shift in corporate focus towards oncology. Cephalon and Chiron conducted two pivotal clinical studies of IGF-1 for ALS, and although one study demonstrated efficacy, the second was equivocal, and the product has never been approved by the FDA.
However, in the last few years, two additional companies, Tercica and Insmed, compiled enough clinical trial data to seek FDA approval in the United States. In August 2005, the FDA approved Tercica's IGF-1 drug, Increlex, as replacement therapy for severe primary IGF-1 deficiency based on clinical trial data from 71 patients. In December 2005, the FDA also approved Iplex, Insmed's IGF-1/IGFBP-3 complex. The Insmed drug is injected once a day versus the twice-a-day version that Tercica sells.
Insmed was found to infringe on patents licensed by Tercica, which then sought to get a U.S. district court judge to ban sales of Iplex. To settle patent infringement charges and resolve all litigation between the two companies, in March 2007 Insmed agreed to withdraw Iplex from the U.S. market, leaving Tercica's Increlex as the sole version of IGF-1 available in the United States.
By delivering Iplex in a complex, patients might get the same efficacy with regard to growth rates but experience fewer side effects with less severe hypoglycemia. This medication might emulate IGF-1's endogenous complexing, as in the human body 97–99% of IGF-1 is bound to one of six IGF binding proteins. IGFBP-3 is the most abundant of these binding proteins, accounting for approximately 80% of IGF-1 binding.
IGFBP-3 is a carrier for IGF-1, meaning that IGF-1 binds IGFBP-3, creating a complex whose combined molecular weight and binding affinity allows the growth factor to have an increased half-life in serum. Without binding to IGFBP-3, IGF-1 is cleared rapidly through the kidney, due to its low molecular weight. But when bound to IGFBP-3, IGF-1 evades renal clearance. Also, since IGFBP-3 has a lower affinity for IGF-1 than IGF-1 has for its receptor, IGFR, its binding does not interfere with IGF-1 function.
In a clinical trial of an investigational compound MK-677, which raises IGF-1 in patients, did not result in an improvement in patients' Alzheimer's symptoms. Another clinical demonstrated that Cephalon's IGF-1 does not slow the progression of weakness in ALS patients, but other studies shown strong beneficial effects of IGF-I replacement therapy in ALS patients, and therefore IGF-I may have the potential to be an effective and safe medicine against ALS, however other studies had conflicting results.
IGF-1 has also been shown to be effective in animal models of stroke when combined with Erythropoietin. Both behavioural and cellular improvements were found.
Numerous sources have claimed that Deer Antler Spray, purportedly extracted from cervid sources, contains IGF-1. Credence to this claim comes from the fact that deer's antlers grow extremely rapidly and that the associated cellular factors can similarly aid in skeletal healing in humans. IGF-1 is currently banned by various sporting bodies. However, sprays and pills claiming to be 'deer antler velvet extracts' are freely available on the market. As IGF-1 is a protein, it cannot be absorbed orally since it is rapidly broken down in the gastrointestinal tract. In September, 2013, the headquarters of SWATS, an infamous distributor of deer antler spray and other controversial products, was raided and ordered to shut down by Alabama's attorney general citing "numerous serious and willful violations of Alabama’s deceptive trade practices act".
Anthony Bosch, of the Biogenesis clinic in Miami, Florida, alleged to have supplied and injected New York Yankee Alex Rodriguez with Insulin-like growth factor 1, along with several other performance enhancing drugs.
Insulin-like growth factor 1 has been shown to bind and interact with all the IGF-1 Binding Proteins (IGFBPs), of which there are six (IGFBP1–6).
^Höppener JW, de Pagter-Holthuizen P, Geurts van Kessel AH, Jansen M, Kittur SD, Antonarakis SE, Lips CJ, Sussenbach JS (1985). "The human gene encoding insulin-like growth factor I is located on chromosome 12". Hum. Genet.69 (2): 157–60. doi:10.1007/BF00293288. PMID2982726.
^Jansen M, van Schaik FM, Ricker AT, Bullock B, Woods DE, Gabbay KH, Nussbaum AL, Sussenbach JS, Van den Brande JL (1983). "Sequence of cDNA encoding human insulin-like growth factor I precursor". Nature306 (5943): 609–11. doi:10.1038/306609a0. PMID6358902.
^Salmon W, Daughaday W (1957). "A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro". J Lab Clin Med49 (6): 825–36. PMID13429201.
^Rinderknecht E, Humbel RE (1978). "The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulin". J Biol Chem253 (8): 2769–2776. PMID632300.
^Miura, Y.; Kato, H.; Noguchi, T. (2007). "Effect of dietary proteins on insulin-like growth factor-1 (IGF-1) messenger ribonucleic acid content in rat liver". British Journal of Nutrition67 (2): 257–265. doi:10.1079/BJN19920029. PMID1596498.edit
^Yilmaz A, Davis ME, RCM Simmen RCM (1999). "Reproductive performance of bulls divergently selected on the basis of blood serum insulin-like growth factor I concentration". J Anim Sci77 (4): 835–9. PMID10328346.
^Carpenter V, Matthews K, Devlin G, Stuart S, Jensen J, Conaglen J, Jeanplong F, Goldspink P, Yang SY, Goldspink G, Bass J, McMahon C (February 2008). "Mechano-growth factor reduces loss of cardiac function in acute myocardial infarction". Heart Lung Circ17 (1): 33–9. doi:10.1016/j.hlc.2007.04.013. PMID17581790.
^Scarth J (2006). "Modulation of the growth hormone-insulin-like growth factor (GH-IGF) axis by pharmaceutical, nutraceutical and environmental xenobiotics: an emerging role for xenobiotic-metabolizing enzymes and the transcription factors regulating their expression. A review". Xenobiotica36 (2–3): 119–218. doi:10.1080/00498250600621627. PMID16702112.
^Friedrich N, Schneider HJ, Haring R, Nauck M, Völzke H, Kroemer HK, Dörr M, Klotsche J, Jung-Sievers C, Pittrow D, Lehnert H, März W, Pieper L, Wittchen HU, Wallaschofski H, Stalla GK (January 2012). "Improved prediction of all-cause mortality by a combination of serum total testosterone and insulin-like growth factor I in adult men". Steroids77 (1–2): 52–8. doi:10.1016/j.steroids.2011.10.005. PMID22037276.
^Jankowska EA, Biel B, Majda J, Szklarska A, Lopuszanska M, Medras M, Anker SD, Banasiak W, Poole-Wilson PA, Ponikowski P (October 2006). "Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival". Circulation114 (17): 1829–37. doi:10.1161/CIRCULATIONAHA.106.649426. PMID17030678.
^Insulin-like growth factor-I: potential for treatment of motor neuronal disorders. Lewis ME, Neff NT, Contreras PC, Stong DB, Oppenheim RW, Grebow PE, Vaught JL.SourceCephalon, Inc., West Chester, Pennsylvania 19380!
^Sevigny JJ, Ryan JM, van Dyck CH, Peng Y, Lines CR, Nessly ML (November 2008). "Growth hormone secretagogue MK-677: no clinical effect on AD progression in a randomized trial". Neurology71 (21): 1702–8. doi:10.1212/01.wnl.0000335163.88054.e7. PMID19015485.
^Nagano I, Shiote M, Murakami T, Kamada H, Hamakawa Y, Matsubara E, Yokoyama M, Moritaz K, Shoji M, Abe K (October 2005). "Beneficial effects of intrathecal IGF-1 administration in patients with amyotrophic lateral sclerosis". Neurol. Res.27 (7): 768–72. doi:10.1179/016164105X39860. PMID16197815.
^Fletcher L, Kohli S, Sprague SM, Scranton RA, Lipton SA, Parra A, Jimenez DF, Digicaylioglu M (July 2009). "Intranasal delivery of erythropoietin plus insulin-like growth factor-I for acute neuroprotection in stroke. Laboratory investigation". J. Neurosurg.111 (1): 164–70. doi:10.3171/2009.2.JNS081199. PMID19284235.
^Amet N, ChenX , Lee H-F, Zaro J, and Shen W-C (2010). "Transferrin Receptor–Mediated Transcytosis in Intestinal Epithelial Cells for Gastrointestinal Absorption of Protein Drugs". In Narang AS, Mahato RM. Targeted Delivery of Small and Macromolecular Drugs. Boca Ratan, Florida: CRC Press/Taylor & Francis Group. p. 32. ISBN142008772X.
^Buckway CK, Wilson EM, Ahlsén M, Bang P, Oh Y, Rosenfeld RG (October 2001). "Mutation of three critical amino acids of the N-terminal domain of IGF-binding protein-3 essential for high affinity IGF binding". J. Clin. Endocrinol. Metab.86 (10): 4943–50. doi:10.1210/jc.86.10.4943. PMID11600567.
^Cohen P, Graves HC, Peehl DM, Kamarei M, Giudice LC, Rosenfeld RG (October 1992). "Prostate-specific antigen (PSA) is an insulin-like growth factor binding protein-3 protease found in seminal plasma". J. Clin. Endocrinol. Metab.75 (4): 1046–53. doi:10.1210/jc.75.4.1046. PMID1383255.
^Twigg SM, Baxter RC (March 1998). "Insulin-like growth factor (IGF)-binding protein 5 forms an alternative ternary complex with IGFs and the acid-labile subunit". J. Biol. Chem.273 (11): 6074–9. doi:10.1074/jbc.273.11.6074. PMID9497324.
^Firth SM, Ganeshprasad U, Baxter RC (January 1998). "Structural determinants of ligand and cell surface binding of insulin-like growth factor-binding protein-3". J. Biol. Chem.273 (5): 2631–8. doi:10.1074/jbc.273.5.2631. PMID9446566.
^Bach LA, Hsieh S, Sakano K, Fujiwara H, Perdue JF, Rechler MM (May 1993). "Binding of mutants of human insulin-like growth factor II to insulin-like growth factor binding proteins 1-6". J. Biol. Chem.268 (13): 9246–54. PMID7683646.
^Qin X, Strong DD, Baylink DJ, Mohan S (September 1998). "Structure-function analysis of the human insulin-like growth factor binding protein-4". J. Biol. Chem.273 (36): 23509–16. doi:10.1074/jbc.273.36.23509. PMID9722589.
^Ahmed S, Yamamoto K, Sato Y, Ogawa T, Herrmann A, Higashi S, Miyazaki K (October 2003). "Proteolytic processing of IGFBP-related protein-1 (TAF/angiomodulin/mac25) modulates its biological activity". Biochem. Biophys. Res. Commun.310 (2): 612–8. doi:10.1016/j.bbrc.2003.09.058. PMID14521955.
^Oh Y, Nagalla SR, Yamanaka Y, Kim HS, Wilson E, Rosenfeld RG (November 1996). "Synthesis and characterization of insulin-like growth factor-binding protein (IGFBP)-7. Recombinant human mac25 protein specifically binds IGF-I and -II". J. Biol. Chem.271 (48): 30322–5. doi:10.1074/jbc.271.48.30322. PMID8939990.
Butler AA, Yakar S, LeRoith D (2002). "Insulin-like growth factor-I: compartmentalization within the somatotropic axis?". News Physiol. Sci.17: 82–5. PMID11909998.
Maccario M, Tassone F, Grottoli S, et al. (2002). "Neuroendocrine and metabolic determinants of the adaptation of GH/IGF-I axis to obesity". Ann. Endocrinol. (Paris)63 (2 Pt 1): 140–4. PMID11994678.
Camacho-Hübner C, Woods KA, Clark AJ, Savage MO (2003). "Insulin-like growth factor (IGF)-I gene deletion". Reviews in endocrine & metabolic disorders3 (4): 357–61. doi:10.1023/A:1020957809082. PMID12424437.
Trojan LA, Kopinski P, Wei MX, et al. (2004). "IGF-I: from diagnostic to triple-helix gene therapy of solid tumors". Acta Biochim. Pol.49 (4): 979–90. PMID12545204.
Winn N, Paul A, Musaró A, Rosenthal N (2003). "Insulin-like growth factor isoforms in skeletal muscle aging, regeneration, and disease". Cold Spring Harb. Symp. Quant. Biol.67: 507–18. doi:10.1101/sqb.2002.67.507. PMID12858577.
Trejo JL, Carro E, Garcia-Galloway E, Torres-Aleman I (2004). "Role of insulin-like growth factor I signaling in neurodegenerative diseases". J. Mol. Med.82 (3): 156–62. doi:10.1007/s00109-003-0499-7. PMID14647921.
Ye P, D'Ercole AJ (2006). "Insulin-like growth factor actions during development of neural stem cells and progenitors in the central nervous system". J. Neurosci. Res.83 (1): 1–6. doi:10.1002/jnr.20688. PMID16294334.
Federico G, Street ME, Maghnie M, et al. (2006). "Assessment of serum IGF-I concentrations in the diagnosis of isolated childhood-onset GH deficiency: a proposal of the Italian Society for Pediatric Endocrinology and Diabetes (SIEDP/ISPED)". J. Endocrinol. Invest.29 (8): 732–7. PMID17033263.
Zakula Z, Koricanac G, Putnikovic B, et al. (2007). "Regulation of the inducible nitric oxide synthase and sodium pump in type 1 diabetes". Med. Hypotheses69 (2): 302–6. doi:10.1016/j.mehy.2006.11.045. PMID17289286.