Theinsulin-like growth factors(IGFs) areproteinswith highsequence similaritytoinsulin.IGFs are part of acomplex systemthat cells use to communicate with theirphysiologicenvironment. This complex system (often referred to as the IGF "axis" ) consists of twocell-surface receptors(IGF1RandIGF2R), twoligands(IGF-1andIGF-2), a family of seven high-affinityIGF-binding proteins(IGFBP1toIGFBP7), as well as associatedIGFBPdegradingenzymes,referred to collectively asproteases.
macromolecular structure
IGF1/GH axis
editThe IGF "axis" is also commonly referred to as the Growth Hormone/IGF-1 Axis.Insulin-like growth factor 1(commonly referred to as IGF-1 or at times usingRoman numeralsas IGF-I) is mainly secreted by the liver as a result of stimulation bygrowth hormone(GH). IGF-1 is important for both the regulation of normal physiology, as well as a number of pathological states, includingcancer.The IGF axis has been shown to play roles in the promotion ofcell proliferationand the inhibition ofcell death(apoptosis).
Insulin-like growth factor 2(IGF-2, at times IGF-II) is thought to be a primarygrowth factorrequired for early development whileIGF-1expression is required for achieving maximal growth.Gene knockoutstudies in mice have confirmed this, though other animals are likely to regulate the expression of these genes in distinct ways. While IGF-2 may be primarilyfetalin action it is also essential for development and function of organs such as thebrain,liver,andkidney.[1]
Factors that are thought to cause variation in the levels of GH and IGF-1 in the circulation include an individual's genetic make-up, the time of day, age, sex, exercise status, stress levels, nutrition level,body mass index(BMI), disease state, race, estrogen status, andxenobioticintake.[2][3][4]
IGF-1 has an involvement in regulatingneural developmentincludingneurogenesis,myelination,synaptogenesis,anddendriticbranching andneuroprotectionafter neuronal damage. Increased serum levels of IGF-I in children have been associated with higherIQ.[5]
IGF-1 shapes the development of thecochleathrough controllingapoptosis.Its deficit can causehearingloss. Serum level of it also underlies a correlation between shortheightand reduced hearing abilities particularly around 3–5 years of age, and at age 18 (latepuberty).[6]
IGF receptors
editThe IGFs are known to bind theIGF-1 receptor,theinsulin receptor,theIGF-2 receptor,the insulin-related receptor and possibly other receptors. The IGF-1 receptor is the "physiological" receptor.IGF-1binds to it at significantly higher affinity than it binds the insulin receptor. Like the insulin receptor, the IGF-1 receptor is areceptor tyrosine kinase—meaning the receptor signals by causing the addition of a phosphate molecule on particular tyrosines. The IGF-2 receptor only binds IGF-2 and acts as a "clearance receptor" —it activates no intracellular signaling pathways, functioning only as an IGF-2 sequestering agent and preventing IGF-2 signaling.[7]
Organs and tissues affected by IGF-1
editSince many distinct tissue types express the IGF-1 receptor, IGF-1's effects are diverse. It acts as aneurotrophicfactor, inducing the survival of neurons. It may catalyseskeletal musclehypertrophy,by inducingprotein synthesis,and by blockingmuscle atrophy.It is protective forcartilagecells, and is associated with activation ofosteocytes,and thus may be an anabolic factor forbone.Since at high concentrations it is capable of activating theinsulin receptor,it can also complement for the effects ofinsulin.[8]Receptors for IGF-1 are found in vascular smooth muscle, while typical receptors for insulin are not found in vascular smooth muscle.[9]
IGF-binding proteins
editIGF-1 and IGF-2 are regulated by a family of proteins known as theIGF-binding proteins.These proteins help to modulate IGF action in complex ways that involve both inhibiting IGF action by preventing binding to the IGF-1 receptor as well as promoting IGF action possibly through aiding in delivery to the receptor and increasing IGF half-life. Currently, there are seven characterized IGF Binding Proteins (IGFBP1 to IGFBP7). There is currently significant data suggesting that IGFBPs play important roles in addition to their ability to regulate IGFs. IGF-1 and IGFBP-3 are GH dependent, whereas IGFBP-1 is insulin regulated. IGFBP-1 production from the liver is significantly elevated during insulinopenia while serum levels of bioactive IGF-1 is increased by insulin.[10]
Diseases affected by IGF
editStudies of recent interest show that the Insulin/IGF axis play an important role inaging.[11]Nematodes,fruit-flies,and other organisms have an increased life span when the gene equivalent to the mammalian insulin isknocked out.It is somewhat difficult to relate this finding to the mammals, however, because in the smaller organism there are many genes (at least 37 in the nematodeCaenorhabditis elegans[12]) that are "insulin-like" or "IGF-1-like", whereas in the mammals insulin-like proteins comprise only seven members (insulin,IGFs,relaxins,EPIL, and relaxin-like factor).[13]The human insulin-like genes have apparently distinct roles with some but less crosstalk presumably because there are multiple insulin-receptor-like proteins in humans. Simpler organisms typically have fewer receptors; for example, only one insulin-like receptor exists in the nematodeC. elegans.[14]Additionally,C. elegansdo not have specialized organs such as the (Islets of Langerhans), which sense insulin in response to glucose homeostasis. Moreover, IGF1 affects lifespan in nematodes by causingdauerformation, a developmental stage ofC. eleganslarva. There is no mammalian correlate. Therefore, it is an open question as to whether either IGF-1 or insulin in the mammal may perturb aging, although there is the suggestion that dietary restriction phenomena may be related.[15]
Other studies are beginning to uncover the important role the IGFs play in diseases such ascanceranddiabetes,showing for instance that IGF-1 stimulates growth of both prostate and breast cancer cells. Researchers are not in complete agreement about the degree of cancer risk that IGF-1 poses.[16]
See also
editReferences
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- ^Takahashi Y, Kipnis DM, Daughaday WH (September 1968)."Growth hormone secretion during sleep".The Journal of Clinical Investigation.47(9):2079–90.doi:10.1172/JCI105893.PMC297368.PMID5675428.
- ^Giustina A, Mazziotti G, Canalis E (August 2008)."Growth hormone, insulin-like growth factors, and the skeleton".Endocrine Reviews.29(5):535–59.doi:10.1210/er.2007-0036.PMC2726838.PMID18436706.
- ^Sutton J, Lazarus L (October 1976). "Growth hormone in exercise: comparison of physiological and pharmacological stimuli".Journal of Applied Physiology.41(4):523–7.doi:10.1152/jappl.1976.41.4.523.PMID985395.
- ^Gunnell D, Miller LL, Rogers I, Holly JM (November 2005). "Association of insulin-like growth factor I and insulin-like growth factor-binding protein-3 with intelligence quotient among 8- to 9-year-old children in the Avon Longitudinal Study of Parents and Children".Pediatrics.116(5): e681-6.doi:10.1542/peds.2004-2390.PMID16263982.
- ^Welch D, Dawes PJ (October 2007)."Childhood hearing is associated with growth rates in infancy and adolescence".Pediatric Research.62(4):495–8.doi:10.1203/PDR.0b013e3181425869.PMID17667854.
- ^Rosenzweig, Steven A.; Atreya, Hanudatta S. (2010-10-15)."Defining the pathway to insulin-like growth factor system targeting in cancer".Biochemical Pharmacology.80(8):1115–1124.doi:10.1016/j.bcp.2010.06.013.ISSN0006-2952.PMC2934757.PMID20599789.
- ^Boucher, Jeremie; Tseng, Yu-Hua; Kahn, C. Ronald (2010-05-28)."Insulin and Insulin-like Growth Factor-1 Receptors Act as Ligand-specific Amplitude Modulators of a Common Pathway Regulating Gene Transcription".The Journal of Biological Chemistry.285(22):17235–17245.doi:10.1074/jbc.M110.118620.ISSN0021-9258.PMC2878077.PMID20360006.
- ^Bornfeldt KE, Arnqvist HJ, Dahlkvist HH, Skottner A, Wikberg JE (April 1988). "Receptors for insulin-like growth factor-I in plasma membranes isolated from bovine mesenteric arteries".Acta Endocrinologica.117(4):428–34.doi:10.1530/acta.0.1170428.PMID2968745.
- ^Brismar, K.; Fernqvist-Forbes, E.; Wahren, J.; Hall, K. (1994)."Effect of insulin on the hepatic production of insulin-like growth factor-binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes".The Journal of Clinical Endocrinology and Metabolism.79(3):872–878.doi:10.1210/jcem.79.3.7521354.ISSN0021-972X.PMID7521354.
- ^Kenyon CJ (March 2010). "The genetics of ageing".Nature.464(7288):504–12.Bibcode:2010Natur.464..504K.doi:10.1038/nature08980.PMID20336132.S2CID2781311.
- ^ Pierce SB, Costa M, Wisotzkey R, Devadhar S, Homburger SA, Buchman AR, et al. (March 2001)."Regulation of DAF-2 receptor signaling by human insulin and ins-1, a member of the unusually large and diverse C. elegans insulin gene family".Genes & Development.15(6):672–86.doi:10.1101/gad.867301.PMC312654.PMID11274053.
- ^Honnen, Sebastian J.; Büchter, Christian; Schröder, Verena; Hoffmann, Michael; Kohara, Yuji; Kampkötter, Andreas; Bossinger, Olaf (2012-02-16)."C. elegans VANG-1 Modulates Life Span via Insulin/IGF-1-Like Signaling".PLOS ONE.7(2): e32183.Bibcode:2012PLoSO...732183H.doi:10.1371/journal.pone.0032183.ISSN1932-6203.PMC3281126.PMID22359667.
- ^Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G (August 1997). "daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans".Science.277(5328):942–6.doi:10.1126/science.277.5328.942.PMID9252323.
- ^Venz, Richard; Pekec, Tina; Katic, Iskra; Ciosk, Rafal; Ewald, Collin Yvès (2021-09-10)."End-of-life targeted degradation of DAF-2 insulin/IGF-1 receptor promotes longevity free from growth-related pathologies".eLife.10:e71335.doi:10.7554/eLife.71335.ISSN2050-084X.PMC8492056.PMID34505574.
- ^ Woods AG, Guthrie KM, Kurlawalla MA, Gall CM (April 1998). "Deafferentation-induced increases in hippocampal insulin-like growth factor-1 messenger RNA expression are severely attenuated in middle aged and aged rats".Neuroscience.83(3):663–8.doi:10.1016/S0306-4522(97)00539-3.PMID9483550.S2CID208782267.