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Insulin-like growth factor 1 (somatomedin C)

PDB rendering based on 1bqt.
Available structures
1bqt, 1gzr, 1gzy, 1gzz, 1h02, 1h59, 1imx, 1pmx, 1wqj, 2dsp, 2dsq, 2dsr, 2gf1, 3gf1, 3lri
Identifiers
Symbols IGF1; IGFI
External IDs OMIM147440 MGI96432 HomoloGene515 GeneCards: IGF1 Gene
RNA expression pattern
PBB GE IGF1 209541 at.png
PBB GE IGF1 209540 at.png
PBB GE IGF1 209542 x at.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 3479 16000
Ensembl ENSG00000017427 ENSMUSG00000020053
UniProt P01343 Q4VJC0
RefSeq (mRNA) NM_000618 NM_010512
RefSeq (protein) NP_000609 NP_034642
Location (UCSC) Chr 12:
101.31 - 101.4 Mb
Chr 10:
87.29 - 87.36 Mb
PubMed search [1] [2]

Insulin-like growth factor 1 (IGF-1), which was once called somatomedin C, is a polypeptide protein hormone similar in molecular structure to insulin. It plays an important role in childhood growth and continues to have anabolic effects in adults.

Contents

Production and circulation

IGF-1 consists of 70 amino acids in a single chain with three intramolecular disulfide bridges. IGF-1 has a molecular weight of 7649 daltons. 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 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.[1]

Action

Its primary action is mediated by binding to its specific receptor, the Insulin-like growth factor 1 receptor, abbreviated as ""IGF1R"", present on many cell types in many tissues. Binding to the IGF1R, a receptor tyrosine kinase, initiates intracellular signaling; 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.

IGF-1 is a primary mediator of the effects of growth hormone (GH). Growth Hormone is made in the pituitary gland, is released into the blood stream, and then stimulates the liver to produce IGF-1. IGF-1 then stimulates systemic body growth, and has growth-promoting effects on almost every cell in the body, especially skeletal muscle, cartilage, bone, liver, kidney, nerves, skin, hematopoietic cell, and lungs. In addition to the insulin-like effects, IGF-1 can also regulate cell growth and development, especially in nerve cells, as well as cellular DNA synthesis.

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's disease, or Laron's dwarfism, are treated with recombinant IGF-1.

IGF-2 and Insulin; 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 II Receptor" (also called the Mannose-6 phosphate receptor). The insulin 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.

IGF-1, daf2 and Regulation of Aging

The daf-2 gene encodes an insulin-like receptor in the worm C. elegans. Mutations in daf-2 have been shown by Cynthia Kenyon to double the lifespan of the worms.[2] The gene is known to regulate reproductive development, aging, resistance to oxidative stress, thermotolerance, resistance to hypoxia, and also resistance to bacterial pathogens.[3]

DAF-2 is the only insulin/IGF-1 like receptor in the worm. Insulin/IGF-1-like signaling is conserved from worms to humans. DAF-2 acts to negatively regulate the forkhead transcription factor DAF-16 through a phosphorylation cascade. Genetic analysis reveals that DAF-16 is required for daf-2-dependent lifespan extension and dauer formation. When not phosphorylated, DAF-16 is active and present in the nucleus.

Receptors

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 IGF-1 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.

Use as a diagnostic test

IGF-1 levels can be measured in the blood in 10-1000 ng/ml amounts. As levels do not fluctuate greatly throughout the day for an individual person, IGF-1 is used by physicians as a screening test for growth hormone deficiency and excess.

Interpretation of IGF-1 levels is complicated by the wide normal ranges, and 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.

Diseases of deficiency and resistance

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.

The IGF signaling pathway appears to play a crucial role in cancer. Several studies have shown that increased levels of IGF lead to an increased risk of cancer. Studies done on lung cancer cells show that drugs inhibiting such signaling can be of potential interest in cancer therapy.[4]

Factors influencing the levels of IGF-1 in the circulation

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.[5] 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.

IGF-1 as a therapeutic agent

3-d model of IGF-1

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 indications, including growth failure, 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.

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.

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. [3] To settle patent infringement charges and resolve all litigation between the two companies, Insmed in March 2007 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. [4]

On 18 November, 2008, Merck announced that their investigational compound MK-677, which raises IGF-1 in patients, did not result in an improvement in patients' Alzheimer's symptoms. [5]

On 25 November, 2008, results of a new study were released showing that Cephalon's IGF-1 does not slow the progression of weakness in ALS patients. Previous shorter studies had conflicting results. [6]

Terminology

IGF-1 has been known as "sulfation factor"[6] and its effects were termed "nonsuppressible insulin-like activity" (NSILA) in the 1970s. It was also known as "somatomedin C" in the 1980s.

Interactions

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). Specific references are provided for interactions with IGFBP7,[7][8] IGFBP3[9][10][11][12][13][14] and IGFBP4.[15][16].

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. For these reasons, an IGF-1/IGFBP-3 combination approach was approved for human treatment... brought forward by a small company called Insmed. However, Insmed fell afoul patent issues, and was ordered to desist in this approach.

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.

References

  1. ^ Miura, Y.; Kato, H.; Noguchi, T. (1992). "Effect of dietary proteins on insulin-like growth factor-1 (IGF-1) messenger ribonucleic acid content in rat liver". British Journal of Nutrition 67 (2): 257. doi:10.1079/BJN19920029. PMID 1596498.   edit
  2. ^ See publications documenting series of experiments at Cynthia Kenyon lab, in particular, Jennie B. Dorman, Bella Albinder, Terry Shroyer & Cynthia Kenyon, "The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans," Genetics, volume 141, number 4, pages 1399-1406 (1995); and Javier Apfeld & Cynthia Kenyon, "Cell non-autonomy of C. elegans daf-2 function in the regulation of diapause and lifespan," Cell, v. 95, n.2, pp.199-210 (1998).
  3. ^ Minaxi S Gami and Catherine A Wolkow (2006). "Studies of Caenorhabditis elegans DAF-2/insulin signaling reveal targets for pharmacological manipulation of lifespan". Aging Cell 5 (1): 31. doi:10.1111/j.1474-9726.2006.00188.x. PMID 16441841. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16441841.  
  4. ^ Velcheti V, Govindan R (2006). "Insulin-like growth factor and lung cancer". Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 1 (7): 607–10. PMID 17409926. http://www.jto.org/pt/re/jto/fulltext.01243894-200609000-00002.htm.  
  5. ^ 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". Xenobiotica 36 (2-3): 119–218. PMID 16702112.  
  6. ^ Salmon W, Daughaday W (1957). "A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro". J Lab Clin Med 49 (6): 825–36. PMID 13429201.  
  7. ^ Ahmed, Sanjida; Yamamoto Kazuhiro, Sato Yuichiro, Ogawa Takashi, Herrmann Andreas, Higashi Shouichi, Miyazaki Kaoru (Oct. 2003). "Proteolytic processing of IGFBP-related protein-1 (TAF/angiomodulin/mac25) modulates its biological activity". Biochem. Biophys. Res. Commun. (United States) 310 (2): 612–8. ISSN 0006-291X. PMID 14521955.  
  8. ^ Oh, Y; Nagalla S R, Yamanaka Y, Kim H S, Wilson E, Rosenfeld R G (Nov. 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. (UNITED STATES) 271 (48): 30322–5. ISSN 0021-9258. PMID 8939990.  
  9. ^ Liu, Bingrong; Weinzimer Stuart A, Gibson Tara Beers, Mascarenhas Desmond, Cohen Pinchas. "Type Ialpha collagen is an IGFBP-3 binding protein". Growth Horm. IGF Res. (Scotland) 13 (2-3): 89–97. ISSN 1096-6374. PMID 12735930.  
  10. ^ Ueki, I; Ooi G T, Tremblay M L, Hurst K R, Bach L A, Boisclair Y R (Jun. 2000). "Inactivation of the acid labile subunit gene in mice results in mild retardation of postnatal growth despite profound disruptions in the circulating insulin-like growth factor system". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 97 (12): 6868–73. doi:10.1073/pnas.120172697. ISSN 0027-8424. PMID 10823924.  
  11. ^ Buckway, C K; Wilson E M, Ahlsén M, Bang P, Oh Y, Rosenfeld R G (Oct. 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. (United States) 86 (10): 4943–50. ISSN 0021-972X. PMID 11600567.  
  12. ^ Cohen, P; Graves H C, Peehl D M, Kamarei M, Giudice L C, Rosenfeld R G (Oct. 1992). "Prostate-specific antigen (PSA) is an insulin-like growth factor binding protein-3 protease found in seminal plasma". J. Clin. Endocrinol. Metab. (UNITED STATES) 75 (4): 1046–53. ISSN 0021-972X. PMID 1383255.  
  13. ^ Twigg, S M; Baxter R C (Mar. 1998). "Insulin-like growth factor (IGF)-binding protein 5 forms an alternative ternary complex with IGFs and the acid-labile subunit". J. Biol. Chem. (UNITED STATES) 273 (11): 6074–9. ISSN 0021-9258. PMID 9497324.  
  14. ^ Firth, S M; Ganeshprasad U, Baxter R C (Jan. 1998). "Structural determinants of ligand and cell surface binding of insulin-like growth factor-binding protein-3". J. Biol. Chem. (UNITED STATES) 273 (5): 2631–8. ISSN 0021-9258. PMID 9446566.  
  15. ^ Bach, L A; Hsieh S, Sakano K, Fujiwara H, Perdue J F, Rechler M M (May. 1993). "Binding of mutants of human insulin-like growth factor II to insulin-like growth factor binding proteins 1-6". J. Biol. Chem. (UNITED STATES) 268 (13): 9246–54. ISSN 0021-9258. PMID 7683646.  
  16. ^ Qin, X; Strong D D, Baylink D J, Mohan S (Sep. 1998). "Structure-function analysis of the human insulin-like growth factor binding protein-4". J. Biol. Chem. (UNITED STATES) 273 (36): 23509–16. ISSN 0021-9258. PMID 9722589.  

Venkatasubramanian G, Chittiprol S, Neelakantachar N et al. Insulin and insulin-like growth factor-1 abnormalities in antipsychotic-naive schizophrenia. Am J Psychiatry 2007;164:1557–1560. Links

Further reading

  • Butler AA, Yakar S, LeRoith D (2002). "Insulin-like growth factor-I: compartmentalization within the somatotropic axis?". News Physiol. Sci. 17: 82–5. PMID 11909998.  
  • 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. PMID 11994678.  
  • Camacho-Hübner C, Woods KA, Clark AJ, Savage MO (2003). "Insulin-like growth factor (IGF)-I gene deletion". Reviews in endocrine & metabolic disorders 3 (4): 357–61. doi:10.1023/A:1020957809082. PMID 12424437.  
  • 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. doi:024904979 (inactive 2008-06-21). PMID 12545204.  
  • 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. PMID 12858577.  
  • Delafontaine P, Song YH, Li Y (2005). "Expression, regulation, and function of IGF-1, IGF-1R, and IGF-1 binding proteins in blood vessels". Arterioscler. Thromb. Vasc. Biol. 24 (3): 435–44. doi:10.1161/01.ATV.0000105902.89459.09. PMID 14604834.  
  • 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. PMID 14647921.  
  • Rabinovsky ED (2004). "The multifunctional role of IGF-1 in peripheral nerve regeneration". Neurol. Res. 26 (2): 204–10. doi:10.1179/016164104225013851. PMID 15072640.  
  • Rincon M, Muzumdar R, Atzmon G, Barzilai N (2005). "The paradox of the insulin/IGF-1 signaling pathway in longevity". Mech. Ageing Dev. 125 (6): 397–403. doi:10.1016/j.mad.2004.03.006. PMID 15272501.  
  • Conti E, Carrozza C, Capoluongo E, et al. (2005). "Insulin-like growth factor-1 as a vascular protective factor". Circulation 110 (15): 2260–5. doi:10.1161/01.CIR.0000144309.87183.FB. PMID 15477425.  
  • Wood AW, Duan C, Bern HA (2005). "Insulin-like growth factor signaling in fish". Int. Rev. Cytol. 243: 215–85. doi:10.1016/S0074-7696(05)43004-1. PMID 15797461.  
  • Sandhu MS (2005). "Insulin-like growth factor-I and risk of type 2 diabetes and coronary heart disease: molecular epidemiology". Endocrine development 9: 44–54. doi:10.1159/000085755. PMID 15879687.  
  • 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. PMID 16294334.  
  • Gómez JM (2006). "The role of insulin-like growth factor I components in the regulation of vitamin D". Current pharmaceutical biotechnology 7 (2): 125–32. doi:10.2174/138920106776597621. PMID 16724947.  
  • 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. PMID 17033263.  
  • Zakula Z, Koricanac G, Putnikovic B, et al. (2007). "Regulation of the inducible nitric oxide synthase and sodium pump in type 1 diabetes". Med. Hypotheses 69 (2): 302–6. doi:10.1016/j.mehy.2006.11.045. PMID 17289286.  
  • Trojan J, Cloix JF, Ardourel MY, et al. (2007). "Insulin-like growth factor type I biology and targeting in malignant gliomas". Neuroscience 145 (3): 795–811. doi:10.1016/j.neuroscience.2007.01.021. PMID 17320297.  

External links

Venkatasubramanian G, Chittiprol S, Neelakantachar N et al. Insulin and insulin-like growth factor-1 abnormalities in antipsychotic-naive schizophrenia. Am J Psychiatry 2007;164:1557–1560.

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edit
Insulin-like growth factor 1
(somatomedin C)

PDB rendering based on 1bqt.
Identifiers
SymbolsIGF1; IGFI
External IDsOMIM147440 MGI96432 HomoloGene515 GeneCards: IGF1 Gene
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez347916000
EnsemblENSG00000017427ENSMUSG00000020053
UniProtP01343Q4VJC0
RefSeq (mRNA)NM_000618NM_010512
RefSeq (protein)NP_000609NP_034642
Location (UCSC)Chr 12:
101.31 - 101.4 Mb
Chr 10:
87.29 - 87.36 Mb
PubMed search[1][2]

Insulin-like growth factor 1 (IGF-1) also known as somatomedin C or mechano growth factor is a protein that in humans is encoded by the IGF1 gene.[1][2] IGF-1 has also been referred to as a "sulfation factor"[3] and its effects were termed "nonsuppressible insulin-like activity" (NSILA) in the 1970s.

IGF-1 is a hormone similar in molecular structure to insulin. It plays an important role in childhood growth and continues to have anabolic effects in adults. A synthetic analog of IGF-1, mecasermin is used for the treatment of growth failure.[4]

IGF-1 consists of 70 amino acids in a single chain with three intramolecular disulfide bridges. IGF-1 has a molecular weight of 7649 daltons.

Contents

Synthesis and circulation

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.[5]

Mechanism of action

Its primary action is mediated by binding to its specific receptor, the Insulin-like growth factor 1 receptor, abbreviated as ""IGF1R"", present on many cell types in many tissues. Binding to the IGF1R, a receptor tyrosine kinase, initiates intracellular signaling; 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.

IGF-1 is a primary mediator of the effects of growth hormone (GH). Growth hormone is made in the anterior pituitary gland, is released into the blood stream, and then stimulates the liver to produce IGF-1. IGF-1 then stimulates systemic body growth, and has growth-promoting effects on almost every cell in the body, especially skeletal muscle, cartilage, bone, liver, kidney, nerves, skin, hematopoietic cell, and lungs. In addition to the insulin-like effects, IGF-1 can also regulate cell growth and development, especially in nerve cells, as well as cellular DNA synthesis.

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.

Receptors

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 IGF-1 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 II receptor" (also called the mannose-6 phosphate receptor). The insulin 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.

Regulation of aging

The daf-2 gene encodes an insulin-like receptor in the worm C. elegans. Mutations in daf-2 have been shown by Cynthia Kenyon to double the lifespan of the worms.[6] The gene is known to regulate reproductive development, aging, resistance to oxidative stress, thermotolerance, resistance to hypoxia, and also resistance to bacterial pathogens.[7]

DAF-2 is the only insulin/IGF-1 like receptor in the worm. Insulin/IGF-1-like signaling is conserved from worms to humans. DAF-2 acts to negatively regulate the forkhead transcription factor DAF-16 through a phosphorylation cascade. Genetic analysis reveals that DAF-16 is required for daf-2-dependent lifespan extension and dauer formation. When not phosphorylated, DAF-16 is active and present in the nucleus.

Factors influencing the levels in the circulation

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.[8] 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.

Diseases of deficiency and resistance

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.

The IGF signaling pathway appears to play a crucial role in cancer. Several studies have shown that increased levels of IGF lead to an increased risk of cancer. Studies done on lung cancer cells show that drugs inhibiting such signaling can be of potential interest in cancer therapy.[9]

Use as a diagnostic test

IGF-1 levels can be measured in the blood in 10-1000 ng/ml amounts. As levels do not fluctuate greatly throughout the day for an individual person, IGF-1 is used by physicians as a screening test for growth hormone deficiency and excess in acromegaly and gigantism.

Interpretation of IGF-1 levels is complicated by the wide normal ranges, and 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.[10] 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[citation needed] 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.[11] To settle patent infringement charges and resolve all litigation between the two companies, Insmed in March 2007 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.[12]

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[citation needed]. 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[citation needed]. IGFBP-3 is the most abundant of these binding proteins, accounting for approximately 80% of IGF-1 binding.

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.[13] Another clinical demonstrated that Cephalon's IGF-1 does not slow the progression of weakness in ALS patients. Previous shorter studies had conflicting results.[14]

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. For these reasons, an IGF-1/IGFBP-3 combination approach was approved for human treatment... brought forward by a small company called Insmed. However, Insmed fell afoul patent issues, and was ordered to desist in this approach.

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.[15]

Interactions

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).

Specific references are provided for interactions with IGFBP3,[16][17][18][19][20][21] IGFBP4,[22][23] and IGFBP7.[24][25]

References

  1. ^ Höppener JW, de Pagter-Holthuizen P, Geurts van Kessel AH, Jansen M, Kittur SD, Antonarakis SE, Lips CJ, Sussenbach JS (1985). [Expression error: Unexpected < operator "The human gene encoding insulin-like growth factor I is located on chromosome 12"]. Hum. Genet. 69 (2): 157–60. doi:10.1007/BF00293288. PMID 2982726. 
  2. ^ Jansen M, van Schaik FM, Ricker AT, Bullock B, Woods DE, Gabbay KH, Nussbaum AL, Sussenbach JS, Van den Brande JL (1983). [Expression error: Unexpected < operator "Sequence of cDNA encoding human insulin-like growth factor I precursor"]. Nature 306 (5943): 609–11. doi:10.1038/306609a0. PMID 6358902. 
  3. ^ Salmon W, Daughaday W (1957). [Expression error: Unexpected < operator "A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro"]. J Lab Clin Med 49 (6): 825–36. PMID 13429201. 
  4. ^ Keating GM (2008). [Expression error: Unexpected < operator "Mecasermin"]. BioDrugs 22 (3): 177–88. doi:10.2165/00063030-200822030-00004. PMID 18481900. 
  5. ^ Miura, Y.; Kato, H.; Noguchi, T. (1992). [Expression error: Unexpected < operator "Effect of dietary proteins on insulin-like growth factor-1 (IGF-1) messenger ribonucleic acid content in rat liver"]. British Journal of Nutrition 67 (2): 257. doi:10.1079/BJN19920029. PMID 1596498.  edit
  6. ^ See publications documenting series of experiments at Cynthia Kenyon lab, in particular, Dorman JB, Albinder B, Shroyer T, Kenyon C (December 1995). [Expression error: Unexpected < operator "The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans"]. Genetics 141 (4): 1399–406. PMID 8601482. ; and Apfeld J, Kenyon C (October 1998). [Expression error: Unexpected < operator "Cell nonautonomy of C. elegans daf-2 function in the regulation of diapause and life span"]. Cell 95 (2): 199–210. doi:10.1016/S0092-8674(00)81751-1. PMID 9790527. 
  7. ^ Minaxi S Gami and Catherine A Wolkow (2006). "Studies of Caenorhabditis elegans DAF-2/insulin signaling reveal targets for pharmacological manipulation of lifespan". Aging Cell 5 (1): 31. doi:10.1111/j.1474-9726.2006.00188.x. PMID 16441841. PMC 1413578. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16441841. 
  8. ^ Scarth J (2006). [Expression error: Unexpected < operator "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"]. Xenobiotica 36 (2-3): 119–218. doi:10.1080/00498250600621627. PMID 16702112. 
  9. ^ Velcheti V, Govindan R (2006). "Insulin-like growth factor and lung cancer". Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 1 (7): 607–10. PMID 17409926. http://www.jto.org/pt/re/jto/fulltext.01243894-200609000-00002.htm. 
  10. ^ Rosenbloom AL (August 2007). [Expression error: Unexpected < operator "The role of recombinant insulin-like growth factor I in the treatment of the short child"]. Curr. Opin. Pediatr. 19 (4): 458–64. doi:10.1097/MOP.0b013e3282094126. PMID 17630612. 
  11. ^ Pollack A (2007-02-17). "Growth Drug Is Caught Up in Patent Fight". The New York Times. http://www.nytimes.com/2007/02/17/business/17patent.html?_r=1&ref=health. Retrieved 2010-03-28. 
  12. ^ Pollack A (2007-03-07). "To Settle Suit, Maker Agrees to Withdraw Growth Drug". The New York Times. http://www.nytimes.com/2007/03/07/business/07patent.html?ref=health. Retrieved 2010-03-28. 
  13. ^ Sevigny JJ, Ryan JM, van Dyck CH, Peng Y, Lines CR, Nessly ML (November 2008). [Expression error: Unexpected < operator "Growth hormone secretagogue MK-677: no clinical effect on AD progression in a randomized trial"]. Neurology 71 (21): 1702–8. doi:10.1212/01.wnl.0000335163.88054.e7. PMID 19015485. 
  14. ^ Sorenson EJ, Windbank AJ, Mandrekar JN, Bamlet WR, Appel SH, Armon C, Barkhaus PE, Bosch P, Boylan K, David WS, Feldman E, Glass J, Gutmann L, Katz J, King W, Luciano CA, McCluskey LF, Nash S, Newman DS, Pascuzzi RM, Pioro E, Sams LJ, Scelsa S, Simpson EP, Subramony SH, Tiryaki E, Thornton CA (November 2008). [Expression error: Unexpected < operator "Subcutaneous IGF-1 is not beneficial in 2-year ALS trial"]. Neurology 71 (22): 1770–5. doi:10.1212/01.wnl.0000335970.78664.36. PMID 19029516. Lay summary – newswise.com. 
  15. ^ Fletcher L, Kohli S, Sprague SM, Scranton RA, Lipton SA, Parra A, Jimenez DF, Digicaylioglu M (July 2009). [Expression error: Unexpected < operator "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. PMID 19284235. 
  16. ^ Horton JK, Thimmaiah KN, Houghton JA, Horowitz ME, Houghton PJ (June 1989). [Expression error: Unexpected < operator "Modulation by verapamil of vincristine pharmacokinetics and toxicity in mice bearing human tumor xenografts"]. Biochem. Pharmacol. 38 (11): 1727–36. doi:10.1016/0006-2952(89)90405-X. PMID 2735930. 
  17. ^ Ueki I, Ooi GT, Tremblay ML, Hurst KR, Bach LA, Boisclair YR (June 2000). [Expression error: Unexpected < operator "Inactivation of the acid labile subunit gene in mice results in mild retardation of postnatal growth despite profound disruptions in the circulating insulin-like growth factor system"]. Proc. Natl. Acad. Sci. U.S.A. 97 (12): 6868–73. doi:10.1073/pnas.120172697. PMID 10823924. 
  18. ^ Buckway CK, Wilson EM, Ahlsén M, Bang P, Oh Y, Rosenfeld RG (October 2001). [Expression error: Unexpected < operator "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. PMID 11600567. 
  19. ^ Cohen P, Graves HC, Peehl DM, Kamarei M, Giudice LC, Rosenfeld RG (October 1992). [Expression error: Unexpected < operator "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. PMID 1383255. 
  20. ^ Twigg SM, Baxter RC (March 1998). [Expression error: Unexpected < operator "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. PMID 9497324. 
  21. ^ Firth SM, Ganeshprasad U, Baxter RC (January 1998). [Expression error: Unexpected < operator "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. PMID 9446566. 
  22. ^ Bach LA, Hsieh S, Sakano K, Fujiwara H, Perdue JF, Rechler MM (May 1993). [Expression error: Unexpected < operator "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. PMID 7683646. 
  23. ^ Qin X, Strong DD, Baylink DJ, Mohan S (September 1998). [Expression error: Unexpected < operator "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. PMID 9722589. 
  24. ^ Ahmed S, Yamamoto K, Sato Y, Ogawa T, Herrmann A, Higashi S, Miyazaki K (October 2003). [Expression error: Unexpected < operator "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. PMID 14521955. 
  25. ^ Oh Y, Nagalla SR, Yamanaka Y, Kim HS, Wilson E, Rosenfeld RG (November 1996). [Expression error: Unexpected < operator "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. PMID 8939990. 

Further reading

  • Butler AA, Yakar S, LeRoith D (2002). [Expression error: Unexpected < operator "Insulin-like growth factor-I: compartmentalization within the somatotropic axis?"]. News Physiol. Sci. 17: 82–5. PMID 11909998. 
  • Maccario M, Tassone F, Grottoli S, et al. (2002). [Expression error: Unexpected < operator "Neuroendocrine and metabolic determinants of the adaptation of GH/IGF-I axis to obesity"]. Ann. Endocrinol. (Paris) 63 (2 Pt 1): 140–4. PMID 11994678. 
  • Camacho-Hübner C, Woods KA, Clark AJ, Savage MO (2003). [Expression error: Unexpected < operator "Insulin-like growth factor (IGF)-I gene deletion"]. Reviews in endocrine & metabolic disorders 3 (4): 357–61. doi:10.1023/A:1020957809082. PMID 12424437. 
  • Trojan LA, Kopinski P, Wei MX, et al. (2004). [Expression error: Unexpected < operator "IGF-I: from diagnostic to triple-helix gene therapy of solid tumors"]. Acta Biochim. Pol. 49 (4): 979–90. PMID 12545204. 
  • Winn N, Paul A, Musaró A, Rosenthal N (2003). [Expression error: Unexpected < operator "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. PMID 12858577. 
  • Delafontaine P, Song YH, Li Y (2005). [Expression error: Unexpected < operator "Expression, regulation, and function of IGF-1, IGF-1R, and IGF-1 binding proteins in blood vessels"]. Arterioscler. Thromb. Vasc. Biol. 24 (3): 435–44. doi:10.1161/01.ATV.0000105902.89459.09. PMID 14604834. 
  • Trejo JL, Carro E, Garcia-Galloway E, Torres-Aleman I (2004). [Expression error: Unexpected < operator "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. PMID 14647921. 
  • Rabinovsky ED (2004). [Expression error: Unexpected < operator "The multifunctional role of IGF-1 in peripheral nerve regeneration"]. Neurol. Res. 26 (2): 204–10. doi:10.1179/016164104225013851. PMID 15072640. 
  • Rincon M, Muzumdar R, Atzmon G, Barzilai N (2005). [Expression error: Unexpected < operator "The paradox of the insulin/IGF-1 signaling pathway in longevity"]. Mech. Ageing Dev. 125 (6): 397–403. doi:10.1016/j.mad.2004.03.006. PMID 15272501. 
  • Conti E, Carrozza C, Capoluongo E, et al. (2005). [Expression error: Unexpected < operator "Insulin-like growth factor-1 as a vascular protective factor"]. Circulation 110 (15): 2260–5. doi:10.1161/01.CIR.0000144309.87183.FB. PMID 15477425. 
  • Wood AW, Duan C, Bern HA (2005). [Expression error: Unexpected < operator "Insulin-like growth factor signaling in fish"]. Int. Rev. Cytol. 243: 215–85. doi:10.1016/S0074-7696(05)43004-1. PMID 15797461. 
  • Sandhu MS (2005). [Expression error: Unexpected < operator "Insulin-like growth factor-I and risk of type 2 diabetes and coronary heart disease: molecular epidemiology"]. Endocrine development 9: 44–54. doi:10.1159/000085755. PMID 15879687. 
  • Ye P, D'Ercole AJ (2006). [Expression error: Unexpected < operator "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. PMID 16294334. 
  • Gómez JM (2006). [Expression error: Unexpected < operator "The role of insulin-like growth factor I components in the regulation of vitamin D"]. Current pharmaceutical biotechnology 7 (2): 125–32. doi:10.2174/138920106776597621. PMID 16724947. 
  • Federico G, Street ME, Maghnie M, et al. (2006). [Expression error: Unexpected < operator "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. PMID 17033263. 
  • Zakula Z, Koricanac G, Putnikovic B, et al. (2007). [Expression error: Unexpected < operator "Regulation of the inducible nitric oxide synthase and sodium pump in type 1 diabetes"]. Med. Hypotheses 69 (2): 302–6. doi:10.1016/j.mehy.2006.11.045. PMID 17289286. 
  • Trojan J, Cloix JF, Ardourel MY, et al. (2007). [Expression error: Unexpected < operator "Insulin-like growth factor type I biology and targeting in malignant gliomas"]. Neuroscience 145 (3): 795–811. doi:10.1016/j.neuroscience.2007.01.021. PMID 17320297. 
  • Venkatasubramanian G, Chittiprol S, Neelakantachar N, Naveen MN, Thirthall J, Gangadhar BN, Shetty KT (October 2007). [Expression error: Unexpected < operator "Insulin and insulin-like growth factor-1 abnormalities in antipsychotic-naive schizophrenia"]. Am J Psychiatry 164 (10): 1557–60. doi:10.1176/appi.ajp.2007.07020233. PMID 17898347. 

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