Insulin-like growth factor
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2008-05-22T06:36:53Z
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/* IGF1/GH Axis */
The '''insulin-like growth factors''' (IGFs) are [[polypeptide]]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 (IGF1R and IGF2R), two [[ligand]]s (IGF-1 and IGF-2), a family of six high-affinity IGF binding [[protein]]s (IGFBP 1-6), as well as associated 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/IGF1 Axis. [[Insulin-like growth factor 1]] (IGF-1) 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) is thought to be a primary [[growth factor]] required for early development while [[IGF-I]] 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]].
Factors that are known to cause variation in the levels of GH and IGF-1 in the circulation include an individuals genetic make-up, the time of day, their age, sex, exercise status, stress levels, genetics, nutrition level and body mass index (BMI), disease state, race, estrogen status and [[xenobiotic]] intake
==IGF Targets==
Almost every [[cell (biology)|cell]] in the human body is affected by [[IGF-1]], especially cells in [[muscle]], [[cartilage]], [[bone]], liver, kidney, [[nerve]]s, [[skin]], and [[lungs]].{{Fact|date=November 2007}} 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-2 is secreted by the brain, kidney, [[pancreas]] and muscle in [[mammal]]s.{{Fact|date=November 2007}} It is more specific in action than [[IGF-1]]. In adult humans it is found at 600 times the concentration of insulin.{{Fact|date=November 2007}}
==IGF Receptors==
Further work is required to determine the main [[receptor (biochemistry)|receptors]] used by these growth factors to elicit their effects. The IGF's are known to bind the [[IGF-1 receptor]], the [[insulin receptor]], the IGF-2 receptor, the insulin-related receptor and possible other receptors. The [[IGF-1 receptor]] seems to be the "physiologic" 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 signalling pathways, functioning only as an IGF-2 sequestering agent and preventing IGF-2 signalling.
==IGF Binding Proteins==
IGF-1 and IGF-2 are regulated by a family of proteins known as the [[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 6 characterized IGF Binding Proteins (IGFBP1-6). There is currently significant data suggesting that IGFBPs play important roles in addition to their ability to regulate IGFs.
==Diseases affected by IGF==
Studies of recent interest show that the Insulin/IGF axis play an important role in [[Senescence|aging]]<sup>2</sup>. [[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 mammal, however, because in the smaller organism there are many genes (at least 37 in the nematode <ref>Pierce, et al. Genes and Development 2001</ref>) that are "insulin-like" or "IGF-1-like", whereas in the mammals insulin-like proteins comprise only 7 members ([[insulin]], [[IGFs]], [[relaxins]], [[EPIL]], and [[relaxin-like factor]]) {{Fact|date=December 2007}} and have apparently distinct roles with some but relatively less crosstalk. On the other hand, simpler organisms typically have fewer receptors (only 1 known in the nematode)<ref>ibid.</ref>, and the roles of these other insulins are unknown. Furthermore these animals do not have specialized organs ([[islets of Langerhans]]) which sense insulin in response to glucose homeostasis. Therefore it is an open question as to whether either IGF1 or insulin in the mammal may perturb aging, although there is strong suggestion dietary restriction phenomena are related.
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.
==See also==
*[[Insulin-like growth factor 1]]
*[[Insulin-like growth factor 2]]
*[[Growth hormone treatment]]
*[[HGH controversies]]
==References==
# Cohen, Pinchas, et al. "[http://jcem.endojournals.org/cgi/content/abstract/73/2/401 Insulin-like growth factors (IGFs), IGF receptors, and IGF-binding proteins in primary cultures of prostate epithelial]". ''Journal of Clinical Endocrinology and Metabolism'', Vol. 73, No. 2, 1991, pp. 401-07
# F. Yaghmaie, O. Saeed, S.A. Garan, M.A. Voelker, A.M. Gouw, W. Freitag, H. Sternberg and P.S. Timiras "[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=17034982 Age-dependent loss of insulin-like growth factor-1 receptor immunoreactive cells in the supraoptic hypothalamus is reduced in calorically restricted mice]". ''International Journal of Developmental Neuroscience'', Vol. 24, Issue 7, 2006, pp. 431-436
# Lippman, Marc E. "The development of biological therapies for breast cancer". ''Science'', Vol. 259, [[January 29]] [[1993]], pp. 631-32
# Papa, Vincenzo, et al. "Insulin-like growth factor-I receptors are overexpressed and predict a low risk in human breast cancer". ''Cancer Research'', Vol. 53, 1993, pp. 3736-40
# Scarth, J "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'', Vol. 36, (2-3) pp. 119-218
# Woods, Alisa G. [http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=9483550&ordinalpos=9&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum"Deafferentation-induced increases in hippocampal insulin-like growth factor-1 messenger RNA expression are severely attenuated in middle aged and aged rats.]" ''Neuroscience'', Vol. 83, (3) pp. 663-668
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{{Hormones}}
== External links ==
[[Category:Peptide hormones]]
[[Category:Growth factors]]
[[Category:endocrinology]]
[[de:Insulinähnliche Wachstumsfaktoren]]
[[it:Fattore di crescita insulino-simile]]
[[he:פקטורי גדילה דמויי אינסולין]]
[[ja:インスリン様成長因子]]
[[pl:Insulinopodobny czynnik wzrostu]]