Editing Insulin-like growth factor

{{short description|Proteins similar to insulin that stimulate cell proliferation}}
[[Image:3GF1 Insulin-Like Growth Factor Nmr 10 01.png|thumb|3GF1 insulin-like growth factor{{brk}}macromolecular structure]]

The '''insulin-like growth factors''' ('''IGFs''') are [[protein]]s with high [[Homology (biology)|sequence similarity]] to [[insulin]]. IGFs are part of a [[complex system]] that cells use to communicate with their [[physiology|physiologic]] environment. This complex system (often referred to as the IGF "axis") consists of two [[cell-surface receptor]]s ([[Insulin-like growth factor 1 receptor|IGF1R]] and [[Insulin-like growth factor 2 receptor|IGF2R]]), two [[ligand (biochemistry)|ligand]]s ([[Insulin-like growth factor 1|IGF-1]] and [[Insulin-like growth factor 2|IGF-2]]), a family of seven high-affinity [[Insulin-like growth factor-binding protein|IGF-binding proteins]] ([[IGFBP1]] to [[IGFBP7]]), as well as associated [[Insulin-like growth factor-binding protein|IGFBP]] degrading [[enzyme]]s, referred to collectively as [[protease]]s.

== IGF1/GH axis ==

The 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 using [[Roman numerals]] as IGF-I) is mainly secreted by the liver as a result of stimulation by [[growth hormone]] (GH). IGF-1 is important for both the regulation of normal physiology, as well as a number of pathological states, including [[cancer]]. The IGF axis has been shown to play roles in the promotion of [[cell proliferation]] and the inhibition of [[cell death]] ([[apoptosis]]). 

[[Insulin-like growth factor 2]] (IGF-2, at times IGF-II) is thought to be a primary [[growth factor]] required for early development while [[IGF-1]] expression is required for achieving maximal growth. [[Gene knockout]] studies 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 primarily [[fetus|fetal]] in action it is also essential for development and function of organs such as the [[brain]], [[liver]], and [[kidney]].<ref>{{cite journal|last1=Younis|first1=Shady|date=February 27, 2018|title=The ZBED6–IGF2 axis has a major effect on growth of skeletal muscle and internal organs in placental mammals|journal=PNAS|volume=9|issue=115|pages=E2048–E2057|doi=10.1073/pnas.1719278115|pmid=29440408|pmc=5834713|bibcode=2018PNAS..115E2048Y |doi-access=free}}</ref>

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, and [[xenobiotic]] intake.<ref>{{cite journal | vauthors = Takahashi Y, Kipnis DM, Daughaday WH | title = Growth hormone secretion during sleep | journal = The Journal of Clinical Investigation | volume = 47 | issue = 9 | pages = 2079–90 | date = September 1968 | pmid = 5675428 | pmc = 297368 | doi = 10.1172/JCI105893 }}</ref><ref>{{cite journal | vauthors = Giustina A, Mazziotti G, Canalis E | title = Growth hormone, insulin-like growth factors, and the skeleton | journal = Endocrine Reviews | volume = 29 | issue = 5 | pages = 535–59 | date = August 2008 | pmid = 18436706 | pmc = 2726838 | doi = 10.1210/er.2007-0036 }}</ref><ref>{{cite journal | vauthors = Sutton J, Lazarus L | title = Growth hormone in exercise: comparison of physiological and pharmacological stimuli | journal = Journal of Applied Physiology | volume = 41 | issue = 4 | pages = 523–7 | date = October 1976 | pmid = 985395 | doi = 10.1152/jappl.1976.41.4.523 }}</ref>

IGF-1 has an involvement in regulating [[neural development]] including [[neurogenesis]], [[myelination]], [[synaptogenesis]], and [[Dendrite|dendritic]] branching and [[neuroprotection]] after neuronal damage. Increased serum levels of IGF-I in children have been associated with higher [[IQ]].<ref>{{cite journal | vauthors = Gunnell D, Miller LL, Rogers I, Holly JM | title = 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 | journal = Pediatrics | volume = 116 | issue = 5 | pages = e681-6 | date = November 2005 | pmid = 16263982 | doi = 10.1542/peds.2004-2390 | doi-access =  }}</ref>

IGF-1 shapes the development of the [[cochlea]] through controlling [[apoptosis]]. Its deficit can cause [[hearing (sense)|hearing]] loss. Serum level of it also underlies a correlation between short [[human height|height]] and reduced hearing abilities particularly around 3–5 years of age, and at age 18 (late [[puberty]]).<ref>{{cite journal | vauthors = Welch D, Dawes PJ | title = Childhood hearing is associated with growth rates in infancy and adolescence | journal = Pediatric Research | volume = 62 | issue = 4 | pages = 495–8 | date = October 2007 | pmid = 17667854 | doi = 10.1203/PDR.0b013e3181425869 | doi-access = free }}</ref>

==IGF receptors==
{{Main|Insulin-like growth factor receptor}}
The IGFs are known to bind the [[IGF-1 receptor]], the [[insulin receptor]], the [[insulin-like growth factor 2 receptor|IGF-2 receptor]], the insulin-related receptor and possibly other receptors.  The IGF-1 receptor is the "physiological" receptor. [[IGF-1]] binds to it at significantly higher affinity than it binds the insulin receptor.  Like the insulin receptor, the IGF-1 receptor is a [[receptor 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.<ref>{{Cite journal |last1=Rosenzweig |first1=Steven A. |last2=Atreya |first2=Hanudatta S. |date=2010-10-15 |title=Defining the pathway to insulin-like growth factor system targeting in cancer |journal=Biochemical Pharmacology |volume=80 |issue=8 |pages=1115–1124 |doi=10.1016/j.bcp.2010.06.013 |issn=0006-2952 |pmc=2934757 |pmid=20599789}}</ref>

==Organs and tissues affected by IGF-1==

Since many distinct tissue types express the IGF-1 receptor, IGF-1's effects are diverse.   It acts as a [[neurotrophic]] factor, inducing the survival of neurons.  It may catalyse [[skeletal muscle]] [[hypertrophy]], by inducing [[protein synthesis]], and by blocking [[muscle atrophy]].  It is protective for [[cartilage]] cells, and is associated with activation of [[osteocytes]], and thus may be an anabolic factor for [[bone]].   Since at high concentrations it is capable of activating the [[insulin receptor]], it can also complement for the effects of [[insulin]].<ref>{{Cite journal|last1=Boucher|first1=Jeremie|last2=Tseng|first2=Yu-Hua|last3=Kahn|first3=C. Ronald|date=2010-05-28|title=Insulin and Insulin-like Growth Factor-1 Receptors Act as Ligand-specific Amplitude Modulators of a Common Pathway Regulating Gene Transcription|journal=The Journal of Biological Chemistry|volume=285|issue=22|pages=17235–17245|doi=10.1074/jbc.M110.118620|issn=0021-9258|pmc=2878077|pmid=20360006|doi-access=free}}</ref> Receptors for IGF-1 are found in vascular smooth muscle, while typical receptors for insulin are not found in vascular smooth muscle.<ref name="pmid2968745">{{cite journal | vauthors = Bornfeldt KE, Arnqvist HJ, Dahlkvist HH, Skottner A, Wikberg JE | title = Receptors for insulin-like growth factor-I in plasma membranes isolated from bovine mesenteric arteries | journal = Acta Endocrinologica | volume = 117 | issue = 4 | pages = 428–34 | date = April 1988 | pmid = 2968745 | doi = 10.1530/acta.0.1170428 }}</ref>

== IGF-binding proteins ==

IGF-1 and IGF-2 are regulated by a family of proteins known as the [[Insulin-like growth factor-binding protein|IGF-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.<ref>{{Cite journal |last1=Brismar |first1=K. |last2=Fernqvist-Forbes |first2=E. |last3=Wahren |first3=J. |last4=Hall |first4=K. |title=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 |url=https://pubmed.ncbi.nlm.nih.gov/7521354/ |journal=The Journal of Clinical Endocrinology and Metabolism |year=1994 |volume=79 |issue=3 |pages=872–878 |doi=10.1210/jcem.79.3.7521354 |issn=0021-972X |pmid=7521354}}</ref>

== Diseases affected by IGF ==

Studies of recent interest show that the Insulin/IGF axis play an important role in [[Senescence|aging]].<ref name="The genetics of ageing">{{cite journal | vauthors = Kenyon CJ | title = The genetics of ageing | journal = Nature | volume = 464 | issue = 7288 | pages = 504–12 | date = March 2010 | pmid = 20336132 | doi = 10.1038/nature08980 | bibcode = 2010Natur.464..504K | s2cid = 2781311 }}</ref> [[Nematode]]s, [[Drosophila melanogaster|fruit-flies]], and other organisms have an increased life span when the gene equivalent to the mammalian insulin is [[Gene knockout|knocked 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 nematode ''Caenorhabditis elegans''<ref name="pmid11274053">
{{cite journal | vauthors = Pierce SB, Costa M, Wisotzkey R, Devadhar S, Homburger SA, Buchman AR, Ferguson KC, Heller J, Platt DM, Pasquinelli AA, Liu LX, Doberstein SK, Ruvkun G | display-authors = 6 | title = 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 | journal = Genes & Development | volume = 15 | issue = 6 | pages = 672–86 | date = March 2001 | pmid = 11274053 | pmc = 312654 | doi = 10.1101/gad.867301 }}</ref>) that are "insulin-like" or "IGF-1-like", whereas in the mammals insulin-like proteins comprise only seven members ([[insulin]], IGFs, [[relaxin]]s, EPIL, and relaxin-like factor).<ref>{{Cite journal |last1=Honnen |first1=Sebastian J. |last2=Büchter |first2=Christian |last3=Schröder |first3=Verena |last4=Hoffmann |first4=Michael |last5=Kohara |first5=Yuji |last6=Kampkötter |first6=Andreas |last7=Bossinger |first7=Olaf |date=2012-02-16 |title=C. elegans VANG-1 Modulates Life Span via Insulin/IGF-1-Like Signaling |journal=PLOS ONE |volume=7 |issue=2 |pages=e32183 |doi=10.1371/journal.pone.0032183 |issn=1932-6203 |pmc=3281126 |pmid=22359667|bibcode=2012PLoSO...732183H |doi-access=free }}</ref> 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 nematode ''C. elegans''.<ref>{{cite journal | vauthors = Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G | title = daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans | journal = Science | volume = 277 | issue = 5328 | pages = 942–6 | date = August 1997 | pmid = 9252323 | doi = 10.1126/science.277.5328.942 }}</ref> Additionally, ''C. elegans'' do 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 causing [[Dauer larva|dauer]] formation, a developmental stage of ''C. elegans'' larva. 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.<ref>{{Cite journal |last1=Venz |first1=Richard |last2=Pekec |first2=Tina |last3=Katic |first3=Iskra |last4=Ciosk |first4=Rafal |last5=Ewald |first5=Collin Yvès |date=2021-09-10 |title=End-of-life targeted degradation of DAF-2 insulin/IGF-1 receptor promotes longevity free from growth-related pathologies |journal=eLife |volume=10 |pages=e71335 |doi=10.7554/eLife.71335 |issn=2050-084X |pmc=8492056 |pmid=34505574 |doi-access=free }}</ref>

Other studies are beginning to uncover the important role the IGFs play in diseases such as [[cancer]] and [[diabetes]], 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.<ref name="pmid9483550">
{{cite journal | vauthors = Woods AG, Guthrie KM, Kurlawalla MA, Gall CM | title = Deafferentation-induced increases in hippocampal insulin-like growth factor-1 messenger RNA expression are severely attenuated in middle aged and aged rats | journal = Neuroscience | volume = 83 | issue = 3 | pages = 663–8 | date = April 1998 | pmid = 9483550 | doi = 10.1016/S0306-4522(97)00539-3 | s2cid = 208782267 }}</ref>

== See also ==
* [[Growth hormone treatment]]
* [[HGH controversies]]
* [[Insulin/IGF/Relaxin family]]

==References==
{{Reflist|30em}}

{{Hormones}}
{{Intercellular signaling peptides and proteins}}
{{Growth factor receptor modulators}}

[[Category:Endocrinology]]
[[Category:Hormones of the somatotropic axis]]
[[Category:Insulin-like growth factor receptor agonists]]
[[Category:Peptide hormones]]
[[sv:IGF]]