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Insulin-like growth factor 1

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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.

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 specific IGF receptors present on many cell types in many tissues. The signal is transduced by intracellular events. IGF-1 is one of the most potent natural activators of the AKT signaling pathway, a stimulator of cell growth and multiplication and a potent inhibitor of programmed cell death.

Almost every cell in the human body is affected by IGF-1, especially cells in muscle, cartilage, bone, liver, kidney, nerves, skin, 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.

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 (IGFR), 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 an individual's genetic make-up, the time of day, his or her age, gender, 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[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.

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. [1] 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. [2]

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. [3]

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. [4]

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 interact with IGFBP7,[7][8] IGFBP3[9][10][11][12][13][14] and IGFBP4.[15][16]

References

  1. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:doi:10.1079/BJN19920029, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=doi:10.1079/BJN19920029 instead.
  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.
  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.
  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 (2003). "Proteolytic processing of IGFBP-related protein-1 (TAF/angiomodulin/mac25) modulates its biological activity". Biochem. Biophys. Res. Commun. 310 (2). United States: 612–8. ISSN 0006-291X. PMID 14521955. {{cite journal}}: Check date values in: |year= (help); Cite has empty unknown parameters: |laydate=, |laysource=, and |laysummary= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help); Unknown parameter |quotes= ignored (help)CS1 maint: year (link)
  8. ^ Oh, Y (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). UNITED STATES: 30322–5. ISSN 0021-9258. PMID 8939990. {{cite journal}}: Check date values in: |year= (help); Cite has empty unknown parameters: |laydate=, |laysource=, and |laysummary= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help); Unknown parameter |quotes= ignored (help)CS1 maint: year (link)
  9. ^ Liu, Bingrong. "Type Ialpha collagen is an IGFBP-3 binding protein". Growth Horm. IGF Res. 13 (2–3). Scotland: 89–97. ISSN 1096-6374. PMID 12735930. {{cite journal}}: Cite has empty unknown parameters: |laydate=, |laysource=, |laysummary=, and |month= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |quotes= ignored (help)
  10. ^ Ueki, I (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. 97 (12). UNITED STATES: 6868–73. doi:10.1073/pnas.120172697. ISSN 0027-8424. PMID 10823924. {{cite journal}}: Check date values in: |year= (help); Cite has empty unknown parameters: |laydate=, |laysource=, and |laysummary= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help); Unknown parameter |quotes= ignored (help)CS1 maint: year (link)
  11. ^ Buckway, C K (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). United States: 4943–50. ISSN 0021-972X. PMID 11600567. {{cite journal}}: Check date values in: |year= (help); Cite has empty unknown parameters: |laydate=, |laysource=, and |laysummary= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help); Unknown parameter |quotes= ignored (help)CS1 maint: year (link)
  12. ^ Cohen, P (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). UNITED STATES: 1046–53. ISSN 0021-972X. PMID 1383255. {{cite journal}}: Check date values in: |year= (help); Cite has empty unknown parameters: |laydate=, |laysource=, and |laysummary= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help); Unknown parameter |quotes= ignored (help)CS1 maint: year (link)
  13. ^ Twigg, S M (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). UNITED STATES: 6074–9. ISSN 0021-9258. PMID 9497324. {{cite journal}}: Check date values in: |year= (help); Cite has empty unknown parameters: |laydate=, |laysource=, and |laysummary= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help); Unknown parameter |quotes= ignored (help)CS1 maint: year (link)
  14. ^ Firth, S M (1998). "Structural determinants of ligand and cell surface binding of insulin-like growth factor-binding protein-3". J. Biol. Chem. 273 (5). UNITED STATES: 2631–8. ISSN 0021-9258. PMID 9446566. {{cite journal}}: Check date values in: |year= (help); Cite has empty unknown parameters: |laydate=, |laysource=, and |laysummary= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help); Unknown parameter |quotes= ignored (help)CS1 maint: year (link)
  15. ^ Bach, L A (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). UNITED STATES: 9246–54. ISSN 0021-9258. PMID 7683646. {{cite journal}}: Check date values in: |year= (help); Cite has empty unknown parameters: |laydate=, |laysource=, and |laysummary= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help); Unknown parameter |quotes= ignored (help)CS1 maint: year (link)
  16. ^ Qin, X (1998). "Structure-function analysis of the human insulin-like growth factor binding protein-4". J. Biol. Chem. 273 (36). UNITED STATES: 23509–16. ISSN 0021-9258. PMID 9722589. {{cite journal}}: Check date values in: |year= (help); Cite has empty unknown parameters: |laydate=, |laysource=, and |laysummary= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help); Unknown parameter |quotes= ignored (help)CS1 maint: year (link)

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

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Template:PBB Controls

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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