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{{Infobox gene}}
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{{GNF_Protein_box
| image = PBB_Protein_IGF1_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1bqt.
| Name = Insulin-like growth factor 1 (somatomedin C)
| HGNCid = 5464
| Symbol = IGF1
| AltSymbols =; IGFI
| OMIM = 147440
| ECnumber = 
| Homologene = 515
| MGIid = 96432
| GeneAtlas_image1 = PBB_GE_IGF1_209541_at.png
| GeneAtlas_image2 = PBB_GE_IGF1_209540_at.png
| GeneAtlas_image3 = PBB_GE_IGF1_209542_x_at.png
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| DateOfBotUpdate = 23:51, 14 September 2007 (UTC)
| Function = {{GNF_GO|id=GO:0005159 |text = insulin-like growth factor receptor binding}} {{GNF_GO|id=GO:0005179 |text = hormone activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0008083 |text = growth factor activity}} {{GNF_GO|id=GO:0018445 |text = prothoracicotrophic hormone activity}}
| Component = {{GNF_GO|id=GO:0005576 |text = extracellular region}} {{GNF_GO|id=GO:0005615 |text = extracellular space}}
| Process = {{GNF_GO|id=GO:0001501 |text = skeletal development}} {{GNF_GO|id=GO:0006260 |text = DNA replication}} {{GNF_GO|id=GO:0006916 |text = anti-apoptosis}} {{GNF_GO|id=GO:0006928 |text = cell motility}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007265 |text = Ras protein signal transduction}} {{GNF_GO|id=GO:0007399 |text = nervous system development}} {{GNF_GO|id=GO:0007517 |text = muscle development}} {{GNF_GO|id=GO:0007605 |text = sensory perception of sound}} {{GNF_GO|id=GO:0008284 |text = positive regulation of cell proliferation}} {{GNF_GO|id=GO:0009441 |text = glycolate metabolic process}} {{GNF_GO|id=GO:0009887 |text = organ morphogenesis}} {{GNF_GO|id=GO:0010001 |text = glial cell differentiation}} {{GNF_GO|id=GO:0048009 |text = insulin-like growth factor receptor signaling pathway}} {{GNF_GO|id=GO:0048468 |text = cell development}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 3479
    | Hs_Ensembl = ENSG00000017427
    | Hs_RefseqProtein = NP_000609
    | Hs_RefseqmRNA = NM_000618
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 12
    | Hs_GenLoc_start = 101313809
    | Hs_GenLoc_end = 101398471
    | Hs_Uniprot = P01343
    | Mm_EntrezGene = 16000
    | Mm_Ensembl = ENSMUSG00000020053
    | Mm_RefseqmRNA = NM_010512
    | Mm_RefseqProtein = NP_034642
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 10
    | Mm_GenLoc_start = 87288867
    | Mm_GenLoc_end = 87361600
    | Mm_Uniprot = Q4VJC0
  }}
}}
{{SI}}
__NOTOC__
{{GS}}


'''Insulin-like growth factor 1''' ('''IGF-1'''), also called '''somatomedin C''', is a [[protein]] that in humans is encoded by the ''IGF1'' [[gene]].<ref name="pmid2982726">{{cite journal | vauthors = Höppener JW, de Pagter-Holthuizen P, Geurts van Kessel AH, Jansen M, Kittur SD, Antonarakis SE, Lips CJ, Sussenbach JS | title = The human gene encoding insulin-like growth factor I is located on chromosome 12 | journal = Hum. Genet. | volume = 69 | issue = 2 | pages = 157–60 | year = 1985 | pmid = 2982726 | doi = 10.1007/BF00293288 }}</ref><ref name="pmid6358902">{{cite journal | vauthors = Jansen M, van Schaik FM, Ricker AT, Bullock B, Woods DE, Gabbay KH, Nussbaum AL, Sussenbach JS, Van den Brande JL | title = Sequence of cDNA encoding human insulin-like growth factor I precursor | journal = Nature | volume = 306 | issue = 5943 | pages = 609–11 | year = 1983 | pmid = 6358902 | doi = 10.1038/306609a0 }}</ref> IGF-1 has also been referred to as a "[[sulfation]] factor"<ref>{{cite journal | vauthors = Salmon WD, Daughaday WH | title = A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro | journal = J Lab Clin Med | volume = 49 | issue = 6 | pages = 825–36 | year = 1957 | pmid = 13429201 }}</ref> and its effects were termed "nonsuppressible insulin-like activity" (NSILA) in the 1970s.


IGF-1 is a [[hormone]] similar in [[tertiary structure|molecular structure]] to [[insulin]]. It plays an important role in childhood growth and continues to have [[Anabolism|anabolic]] effects in adults. A synthetic analog of IGF-1, [[mecasermin]],  is used for the treatment of [[growth failure]].<ref name="pmid18481900">{{cite journal | vauthors = Keating GM | title = Mecasermin | journal = BioDrugs | volume = 22 | issue = 3 | pages = 177–88 | year = 2008 | pmid = 18481900 | doi = 10.2165/00063030-200822030-00004 }}</ref>


IGF-1 consists of 70 amino acids in a single chain with three intramolecular disulfide bridges. IGF-1 has a molecular weight of 7,649 [[Dalton (unit)|Daltons]].<ref name="pmid632300">{{cite journal | vauthors = Rinderknecht E, Humbel RE | title = The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulin | journal = J Biol Chem | volume = 253 | issue = 8 | pages = 2769–2776 | year = 1978 | pmid = 632300 }}</ref>


'''Insulin-like growth factor 1 (IGF-1)''' is a  [[polypeptide]] [[protein]] [[hormone]] similar in [[molecular structure]] to [[insulin]]. It plays an important role in childhood growth and continues to have [[Anabolism|anabolic effects]] in adults.  
== Synthesis and circulation ==
{{see also|Neurobiological effects of physical exercise#IGF-1 signaling}}
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 signaling pathway post GH receptor including [[PTPN11|SHP2]] and [[STAT5B]]. Approximately 98% of IGF-1 is always bound to one of 6 binding proteins (IGF-BP). [[IGFBP3|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. IGFBP-1 is regulated by insulin. {{medical citation needed|date=September 2014}}


==Production and circulation==
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.{{mcn|date=September 2014}}
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 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.
[[Image:IGF-1.GIF|thumb|right|3-d model of IGF-1]]


==Action==
Protein intake increases IGF-1 levels in humans, independent of total calorie consumption.<ref name="pmid24606898">{{cite journal |vauthors=Levine ME, Suarez JA, Brandhorst S, Balasubramanian P, Cheng CW, Madia F, Fontana L, Mirisola MG, Guevara-Aguirre J, Wan J, Passarino G, Kennedy BK, Wei M, Cohen P, Crimmins EM, Longo VD | title=Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population | journal=[[Cell Metabolism]] | volume=19 | issue=3 | year=2002| pages=407–417 | url = http://www.cell.com/cell-metabolism/abstract/S1550-4131(14)00062-X | doi= 10.1016/j.cmet.2014.02.006 |pmc = 3988204 | pmid=24606898}}</ref>  Factors that are known to cause variation in the levels of [[growth hormone]] (GH) and IGF-1 in the circulation include: insulin levels, genetic make-up, the time of day, age, sex, exercise status, stress levels, nutrition level and body mass index (BMI), disease state, ethnicity, estrogen status and [[xenobiotic]] intake.<ref>{{cite journal | vauthors = Scarth JP | title = 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 | journal = Xenobiotica | volume = 36 | issue = 2–3 | pages = 119–218 | year = 2006 | pmid = 16702112 | doi = 10.1080/00498250600621627 }}</ref>
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]] [[Signal transduction|signaling pathway]], a stimulator of cell growth and multiplication and a potent inhibitor of [[Apoptosis|programmed cell death]].  


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]]. 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.
== Mechanism of action ==
{{See also|Hypothalamic–pituitary–somatic axis}}


==IGF-2 and Insulin; related growth factors==
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 (biology)|cell]] in the body, especially skeletal  [[muscle]], [[cartilage]], [[bone]], [[liver]], [[kidney]], [[nerve]], [[skin]], [[hematopoietic]], and [[lung]] cells. In addition to the [[insulin]]-like effects, IGF-1 can also regulate cellular [[DNA]] synthesis.<ref>{{cite journal | vauthors = Yakar S, Rosen CJ, Beamer WG, Ackert-Bicknell CL, Wu Y, Liu JL, Ooi GT, Setser J, Frystyk J, Boisclair YR, LeRoith D | title = Circulating levels of IGF-1 directly regulate bone growth and density | journal = Journal of Clinical Investigation | volume = 110 | issue = 6 | pages = 771–781 | year = 2002|doi=10.1172/JCI15463|pmid=12235108|pmc=151128}}</ref>


IGF-1 is closely related to a second protein called "[[Insulin-like growth factor 2|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.
IGF-1 binds to at least two cell surface [[receptor tyrosine kinase]]s: the [[IGF-1 receptor]] (IGF1R), and the [[insulin receptor]].  Its primary action is mediated by binding to its specific receptor, IGF1R, which is present on the surface of many cell types in many tissues. Binding to the IGF1R initiates intracellular signaling. IGF-1 is one of the most potent natural activators of the [[AKT]] [[Signal transduction|signaling pathway]], a stimulator of cell growth and proliferation, and a potent inhibitor of [[Apoptosis|programmed cell death]] .<ref>{{cite journal | vauthors = Peruzzi F, Prisco M, Dews M, Salomoni P, Grassilli E, Romano G, Calabretta B, Baserga R | title = Multiple signaling pathways of the insulin-like growth factor 1 receptor in protection from apoptosis | journal = Molecular and Cellular Biology | volume = 19 | issue = 10 | pages = 7203–15 | date = October 1999 | pmid = 10490655 | pmc = 84713 | doi=10.1128/mcb.19.10.7203}}</ref><ref>{{cite journal | vauthors = Juin P, Hueber AO, Littlewood T, Evan G | title = c-Myc-induced sensitization to apoptosis is mediated through cytochrome c release | journal = Genes & Development | volume = 13 | issue = 11 | pages = 1367–81 | date = June 1999 | pmid = 10364155 | doi=10.1101/gad.13.11.1367| pmc = 316765 }}</ref>  The IGF-1 receptor seems to be the "physiologic" receptor because it binds IGF-1 with significantly higher affinity than insulin receptor does. IGF-1 activates the insulin receptor at approximately  0.1 times 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).{{medical citation needed|date=September 2014}}
 
Insulin-like growth factor 1 receptor (IGF-1R) and other tyrosine kinase growth factor receptors signal through multiple pathways. A key pathway is regulated by phosphatidylinositol-3 kinase (PI3K) and its downstream partner, the mammalian target of [[rapamycin]] (mTOR). Rapamycins complex with FKBPP12 to inhibit the mTORC1 complex. mTORC2 remains unaffected and responds by upregulating Akt, driving signals through the inhibited mTORC1. Phosphorylation of eukaryotic initiation factor 4e (eif-4E) [4EBP] by mTOR inhibits the capacity of 4EBP to inhibit eif-4E and slow metabolism.{{medical citation needed|date=September 2014}}
 
Insulin-like growth factor 1 has been shown to bind and interact with all seven IGF-1 binding proteins (IGFBPs): [[IGFBP1]], [[IGFBP2]], [[IGFBP3]], [[IGFBP4]], [[IGFBP5]], [[IGFBP6]], and [[IGFBP7]].{{medical citation needed|date=September 2014}}
Some IGFBPs are inhibitory.  For example, both [[IGFBP2|IGFBP-2]] and [[IGFBP5|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.{{medical citation needed|date=September 2014}}
 
== Related growth factors ==
 
IGF-1 is closely related to a second protein called "[[Insulin-like growth factor 2|IGF-2]]".  IGF-2 also binds the IGF-1 receptor.  However, IGF-2 alone binds a receptor called the "IGF-2 receptor" (also called the mannose-6 phosphate receptor). The insulin-like 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.
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.


==Receptors==
A [[splice variant]] of IGF-1 sharing an identical mature region, but with a different E domain is known as ''mechano-growth factor'' (MGF).<ref name="pmid17581790">{{cite journal | vauthors = Carpenter V, Matthews K, Devlin G, Stuart S, Jensen J, Conaglen J, Jeanplong F, Goldspink P, Yang SY, Goldspink G, Bass J, McMahon C | title = Mechano-growth factor reduces loss of cardiac function in acute myocardial infarction | journal = Heart Lung Circ | volume = 17 | issue = 1 | pages = 33–9 | date = February 2008 | pmid = 17581790 | doi = 10.1016/j.hlc.2007.04.013 }}</ref>
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.
== Clinical significance ==


==Use as a diagnostic test==
=== Dwarfism ===
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 [[acromegaly|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.
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&nbsp;3 standard deviations (SD), and IGF-1 levels below 3&nbsp;SD. 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.


==Diseases of deficiency and resistance==
People with Laron syndrome have strikingly low rates of cancer and [[diabetes]].<ref name="urlEcuadorean Villagers May Hold Secret to Longevity">{{cite web | url = https://www.nytimes.com/2011/02/17/science/17longevity.html | title = Ecuadorean Villagers May Hold Secret to Longevity | publisher = New York Times | vauthors = Wade N | date = 17 February 2011 }}</ref>
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.<ref>{{cite journal |author=Velcheti V, Govindan R |title=Insulin-like growth factor and lung cancer |journal=Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer |volume=1 |issue=7 |pages=607-10 |year=2006 |pmid=17409926 |doi= |url=http://www.jto.org/pt/re/jto/fulltext.01243894-200609000-00002.htm}}</ref>
=== Acromegaly ===


==Factors influencing the levels of IGF-1 in the circulation==
[[Acromegaly]] is a [[syndrome]] that results when the [[anterior pituitary]] gland produces excess [[growth hormone]] (GH). A number of disorders may increase the pituitary's GH output, although most commonly it involves a tumor called [[pituitary adenoma]], derived from a distinct type of cell ([[somatotroph]]s). It leads to anatomical changes and metabolic dysfunction caused by elevated GH and insulin-like growth factor 1 (IGF-1) levels.<ref name="pmid24566817">{{cite journal | vauthors = Giustina A, Chanson P, Kleinberg D, Bronstein MD, Clemmons DR, Klibanski A, van der Lely AJ, Strasburger CJ, Lamberts SW, Ho KK, Casanueva FF, Melmed S | title = Expert consensus document: A consensus on the medical treatment of acromegaly | journal = Nat Rev Endocrinol | volume = 10 | issue = 4 | pages = 243–8 | year = 2014 | pmid = 24566817 | doi = 10.1038/nrendo.2014.21 }}</ref>


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.<ref>{{cite journal |author=Scarth J |title=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 |journal=Xenobiotica |volume=36 |issue=2-3 |pages=119-218 |year= 2006 |id=PMID 16702112}}</ref> 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]].
=== Diagnostic test ===


==IGF-1 as a therapeutic agent==
IGF-1 levels can be measured in the blood in 10-1000&nbsp;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 [[acromegaly|excess]] in [[acromegaly]] and [[gigantism]].
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.
Interpretation of IGF-1 levels is complicated by the wide normal ranges, and marked 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.


By delivering Iplex in a complex, patients can get the same efficacy with regard to growth rates but experience fewer side effects with less severe hypoglycemia. This would seem to make sense, since 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.
=== As a therapeutic agent ===
Patients with severe primary insulin-like growth factor-1 deficiency (IGFD), called [[Laron syndrome]], may be treated with either IGF-1 alone or in combination with [[IGFBP-3]].<ref name="pmid17630612"/> [[Mecasermin]] (brand name Increlex) is a synthetic analog of IGF-1 which is approved for the treatment of [[growth failure]].<ref name="pmid17630612">{{cite journal | vauthors = Rosenbloom AL | title = The role of recombinant insulin-like growth factor I in the treatment of the short child | journal = Curr. Opin. Pediatr. | volume = 19 | issue = 4 | pages = 458–64 | year = 2007 | pmid = 17630612 | doi = 10.1097/MOP.0b013e3282094126 }}</ref> IGF-1 has been manufactured recombinantly on a large scale using both yeast and ''E. coli''.


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. [http://www.nytimes.com/2007/02/17/business/17patent.html?ref=health] 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. [http://www.nytimes.com/2007/03/07/business/07patent.html?ref=health]
== Research ==


==Terminology==
=== Aging ===
IGF-1 has been known as "sulfation factor"<ref>{{cite journal |author=Salmon W, Daughaday W |title=A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro |journal=J Lab Clin Med |volume=49 |issue=6 |pages=825-36 |year=1957 |id=PMID 13429201}}</ref> and its effects were termed "nonsuppressible insulin-like activity" (NSILA) in the 1970s. It was also known as "somatomedin C" in the 1980s.


==Additional images==
Signaling through the [[insulin]]/IGF-1-like [[receptor (biochemistry)|receptor]] pathway is a significant contributor to [[biological aging]] in many organisms. [[Cynthia Kenyon]] showed that mutations in the [[daf-2]] [[gene]] double the lifespan of the roundworm, ''[[Caenorhabditis elegans|C. elegans]]''.<ref name="pmid8247153">{{cite journal | vauthors = Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R | title = A C. elegans mutant that lives twice as long as wild type | journal = [[Nature (journal)|Nature]] | volume = 366 | issue = 6454 | pages = 461–464 | year = 1993 | pmid = 8247153 | doi = 10.1038/366461a0 }}</ref><ref name="pmid22939742">{{cite journal | vauthors = Lapierre LR, Hansen M | title = Lessons from C. elegans: signaling pathways for longevity | journal = Trends Endocrinol. Metab. | volume = 23 | issue = 12 | pages = 637–44 | year = 2012 | pmid = 22939742 | pmc = 3502657 | doi = 10.1016/j.tem.2012.07.007 }}</ref>  Daf-2 encodes the worm's unified [[insulin]]/IGF-1-like [[receptor (biochemistry)|receptor]]. Despite the impact of IGF1-like on ''C. elegans'' longevity, direct application to mammalian aging is not as clear as mammals lack [[Dauer larva|dauer]] developmental stages. It is also inconsistent with evidence in humans.<ref name=AgingMaleRev />
<gallery>
  Image:IGF-1.gif|IGF-1
</gallery>


==References==
There are mixed reports that IGF-1 signaling modulates the aging process in humans and about whether the direction of its effect is positive or negative.<ref name=AgingMaleRev>{{cite journal | vauthors = Sattler FR | title = Growth hormone in the aging male | journal = Best Pract. Res. Clin. Endocrinol. Metab. | volume = 27 | issue = 4 | pages = 541–55 | date = August 2013 | pmid = 24054930 | doi = 10.1016/j.beem.2013.05.003 | quote = <!-- In animal models, alterations in GH/IGF-1 signaling with reductions in these somatotrophs appear to increase life span. &nbsp;... Administration of IGF-1Eb (mechanogrowth factor) stimulates proliferation of myoblasts and induces muscle hypertrophy. Increases in GH and IGF-1 during adolescence are beneficial for brain and cardiovascular function during the aging process and GH administration during adolescence is vasoprotective and increases life-span.<sup>15</sup>&nbsp;... Studies relating GH and IGF-1 status to longevity provide inconsistent evidence as to whether decreased (somatopause) or high levels (e.g. acromegaly) of these hormones are beneficial or detrimental to longevity.&nbsp;... It is difficult to reconcile the largely protective effects of GH/IGF-1 deficiency on longevity in animals with the inconsistent or deleterious effects of low levels or declining GH/IGF-1 during human aging. -->| pmc = 3940699 }}</ref>
{{reflist}}


==Further reading==
=== Neuropathy ===
{{refbegin | 2}}
{{PBB_Further_reading
| citations =  
*{{cite journal  | author=Butler AA, Yakar S, LeRoith D |title=Insulin-like growth factor-I: compartmentalization within the somatotropic axis? |journal=News Physiol. Sci. |volume=17 |issue=  |pages= 82-5 |year= 2002 |pmid= 11909998 |doi=  }}
*{{cite journal  | author=Maccario M, Tassone F, Grottoli S, ''et al.'' |title=Neuroendocrine and metabolic determinants of the adaptation of GH/IGF-I axis to obesity. |journal=Ann. Endocrinol. (Paris) |volume=63 |issue= 2 Pt 1 |pages= 140-4 |year= 2002 |pmid= 11994678 |doi=  }}
*{{cite journal  | author=Camacho-Hübner C, Woods KA, Clark AJ, Savage MO |title=Insulin-like growth factor (IGF)-I gene deletion. |journal=Reviews in endocrine & metabolic disorders |volume=3 |issue= 4 |pages= 357-61 |year= 2003 |pmid= 12424437 |doi=  }}
*{{cite journal  | author=Trojan LA, Kopinski P, Wei MX, ''et al.'' |title=IGF-I: from diagnostic to triple-helix gene therapy of solid tumors. |journal=Acta Biochim. Pol. |volume=49 |issue= 4 |pages= 979-90 |year= 2004 |pmid= 12545204 |doi= 024904979 }}
*{{cite journal  | author=Winn N, Paul A, Musaró A, Rosenthal N |title=Insulin-like growth factor isoforms in skeletal muscle aging, regeneration, and disease. |journal=Cold Spring Harb. Symp. Quant. Biol. |volume=67 |issue=  |pages= 507-18 |year= 2003 |pmid= 12858577 |doi=  }}
*{{cite journal  | author=Delafontaine P, Song YH, Li Y |title=Expression, regulation, and function of IGF-1, IGF-1R, and IGF-1 binding proteins in blood vessels. |journal=Arterioscler. Thromb. Vasc. Biol. |volume=24 |issue= 3 |pages= 435-44 |year= 2005 |pmid= 14604834 |doi= 10.1161/01.ATV.0000105902.89459.09 }}
*{{cite journal  | author=Trejo JL, Carro E, Garcia-Galloway E, Torres-Aleman I |title=Role of insulin-like growth factor I signaling in neurodegenerative diseases. |journal=J. Mol. Med. |volume=82 |issue= 3 |pages= 156-62 |year= 2004 |pmid= 14647921 |doi= 10.1007/s00109-003-0499-7 }}
*{{cite journal  | author=Rabinovsky ED |title=The multifunctional role of IGF-1 in peripheral nerve regeneration. |journal=Neurol. Res. |volume=26 |issue= 2 |pages= 204-10 |year= 2004 |pmid= 15072640 |doi= 10.1179/016164104225013851 }}
*{{cite journal  | author=Rincon M, Muzumdar R, Atzmon G, Barzilai N |title=The paradox of the insulin/IGF-1 signaling pathway in longevity. |journal=Mech. Ageing Dev. |volume=125 |issue= 6 |pages= 397-403 |year= 2005 |pmid= 15272501 |doi=  }}
*{{cite journal  | author=Conti E, Carrozza C, Capoluongo E, ''et al.'' |title=Insulin-like growth factor-1 as a vascular protective factor. |journal=Circulation |volume=110 |issue= 15 |pages= 2260-5 |year= 2005 |pmid= 15477425 |doi= 10.1161/01.CIR.0000144309.87183.FB }}
*{{cite journal  | author=Wood AW, Duan C, Bern HA |title=Insulin-like growth factor signaling in fish. |journal=Int. Rev. Cytol. |volume=243 |issue=  |pages= 215-85 |year= 2005 |pmid= 15797461 |doi= 10.1016/S0074-7696(05)43004-1 }}
*{{cite journal  | author=Sandhu MS |title=Insulin-like growth factor-I and risk of type 2 diabetes and coronary heart disease: molecular epidemiology. |journal=Endocrine development |volume=9 |issue=  |pages= 44-54 |year= 2005 |pmid= 15879687 |doi= 10.1159/000085755 }}
*{{cite journal  | author=Ye P, D'Ercole AJ |title=Insulin-like growth factor actions during development of neural stem cells and progenitors in the central nervous system. |journal=J. Neurosci. Res. |volume=83 |issue= 1 |pages= 1-6 |year= 2006 |pmid= 16294334 |doi= 10.1002/jnr.20688 }}
*{{cite journal  | author=Gómez JM |title=The role of insulin-like growth factor I components in the regulation of vitamin D. |journal=Current pharmaceutical biotechnology |volume=7 |issue= 2 |pages= 125-32 |year= 2006 |pmid= 16724947 |doi=  }}
*{{cite journal  | author=Federico G, Street ME, Maghnie M, ''et al.'' |title=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). |journal=J. Endocrinol. Invest. |volume=29 |issue= 8 |pages= 732-7 |year= 2006 |pmid= 17033263 |doi=  }}
*{{cite journal  | author=Zakula Z, Koricanac G, Putnikovic B, ''et al.'' |title=Regulation of the inducible nitric oxide synthase and sodium pump in type 1 diabetes. |journal=Med. Hypotheses |volume=69 |issue= 2 |pages= 302-6 |year= 2007 |pmid= 17289286 |doi= 10.1016/j.mehy.2006.11.045 }}
*{{cite journal  | author=Trojan J, Cloix JF, Ardourel MY, ''et al.'' |title=Insulin-like growth factor type I biology and targeting in malignant gliomas. |journal=Neuroscience |volume=145 |issue= 3 |pages= 795-811 |year= 2007 |pmid= 17320297 |doi= 10.1016/j.neuroscience.2007.01.021 }}
}}
{{refend}}


==External links==
Therapeutic administration of neurotrophic proteins (IGF-1) is associated with potential reversal of degeneration of spinal cord motor neuron axons in certain peripheral neuropathies.<ref>{{cite journal | vauthors = Lewis ME, Neff NT, Contreras PC, Stong DB, Oppenheim RW, Grebow PE, Vaught JL | title = Insulin-like growth factor-I: potential for treatment of motor neuronal disorders | journal = Experimental Neurology | volume = 124 | issue = 1 | pages = 73–88 | date = Nov 1993 | pmid = 8282084 | doi = 10.1006/exnr.1993.1177 }}</ref>
 
=== Cancer ===
 
The IGF signaling pathway has been implicated in some forms of cancer.<ref>{{cite journal | vauthors = Arnaldez FI, Helman LJ | title = Targeting the insulin growth factor receptor 1 | journal = Hematology/Oncology Clinics of North America | volume = 26 | issue = 3 | pages = 527–42, vii-viii | date = Jun 2012 | pmid = 22520978 | pmc = 3334849 | doi = 10.1016/j.hoc.2012.01.004 }}</ref><ref name="Yang2012">{{cite journal | vauthors = Yang Y, Yee D | title = Targeting insulin and insulin-like growth factor signaling in breast cancer | journal = Journal of Mammary Gland Biology and Neoplasia | volume = 17 | issue = 3-4 | pages = 251–61 | date = Dec 2012 | pmid = 23054135 | pmc = 3534944 | doi = 10.1007/s10911-012-9268-y }}</ref><!--Ewings-->  People with [[Laron syndrome]], who express low levels of IGF-1, have a greatly reduced risk of developing cancer.<ref name="pmid21459318">{{cite journal | vauthors = Gallagher EJ, LeRoith D | title = Is growth hormone resistance/IGF-1 reduction good for you? | journal = Cell Metab. | volume = 13 | issue = 4 | pages = 355–6 | date = April 2011 | pmid = 21459318 | doi = 10.1016/j.cmet.2011.03.003 }}</ref> Dietary interventions and modifications shown to downregulate IGF-1 activity, such as vegan diets, have been associated with a lower risk of cancer.<ref name="pmid10687887">{{cite journal | vauthors = McCarty MF | title = Vegan proteins may reduce risk of cancer, obesity, and cardiovascular disease by promoting increased glucagon activity | journal = Med. Hypotheses | volume = 53 | issue = 6 | pages = 459–85 | year = 1999 | pmid = 10687887 | doi = 10.1054/mehy.1999.0784 }}</ref> However, despite considerable research, perturbations specific to cancer are incompletely delineated<ref>{{cite journal | vauthors = Siddle K | title = Molecular basis of signaling specificity of insulin and IGF receptors: neglected corners and recent advances | journal = Frontiers in Endocrinology | volume = 3 | issue =  | pages = 34 | year = 2012 | pmid = 22649417 | pmc = 3355962 | doi = 10.3389/fendo.2012.00034 }}</ref><ref>{{cite journal | vauthors = Girnita L, Worrall C, Takahashi S, Seregard S, Girnita A | title = Something old, something new and something borrowed: emerging paradigm of insulin-like growth factor type 1 receptor (IGF-1R) signaling regulation | journal = Cellular and Molecular Life Sciences | volume = 71 | issue = 13 | pages = 2403–27 | date = Jul 2014 | pmid = 24276851 | pmc = 4055838 | doi = 10.1007/s00018-013-1514-y }}</ref> and clinical drug trials have been unsuccessful.<ref name="Yang2012"/><ref name="Singh2014">{{cite journal | vauthors = Singh P, Alex JM, Bast F | title = Insulin receptor (IR) and insulin-like growth factor receptor 1 (IGF-1R) signaling systems: novel treatment strategies for cancer | journal = Medical Oncology | volume = 31 | issue = 1 | pages = 805 | date = Jan 2014 | pmid = 24338270 | doi = 10.1007/s12032-013-0805-3 }}</ref>
 
=== Stroke ===
 
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.<ref name="pmid">{{cite journal | vauthors = Fletcher L, Kohli S, Sprague SM, Scranton RA, Lipton SA, Parra A, Jimenez DF, Digicaylioglu M | title = Intranasal delivery of erythropoietin plus insulin-like growth factor-I for acute neuroprotection in stroke. Laboratory investigation | journal = J. Neurosurg. | volume = 111 | issue = 1 | pages = 164–70 | date = July 2009 | pmid = 19284235 | doi = 10.3171/2009.2.JNS081199 }}</ref>
 
== Clinical trials ==
 
=== Recombinant protein ===
 
Several companies have evaluated IGF-1 in clinical trials for a variety of indications, including [[type 1 diabetes]], [[type 2 diabetes]], [[amyotrophic lateral sclerosis]]  (ALS aka "Lou Gehrig's Disease"),<ref name="pmid8866126">{{cite journal | vauthors = Vaught JL, Contreras PC, Glicksman MA, Neff NT | title = Potential utility of rhIGF-1 in neuromuscular and/or degenerative disease | journal = Ciba Found. Symp. | volume = 196 | issue =  | pages = 18–27; discussion 27–38 | year = 1996 | pmid = 8866126 | doi =  }}</ref> 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.{{medical citation needed|date=January 2015}} However, the sponsor, [[Genentech]], discontinued the program due to an exacerbation of [[diabetic retinopathy]]<ref>{{cite press release | title = Genentech Discontinues IGF-I Drug Development Effort in Diabetes | publisher = Genentech | date = 5 September 1997 | url = http://www.gene.com/media/press-releases/4842/1997-09-05/genentech-discontinues-igf-i-drug-develo | accessdate = 15 March 2013}}</ref> 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,{{medical citation needed|date=January 2015}} and the product has never been approved by the FDA.
 
=== Small molecules that upregulate IGF-1 ===
 
In a clinical trial of an investigational compound [[ibutamoren]], which raises IGF-1 in patients, did not result in an improvement in patients' Alzheimer's symptoms.<ref name="pmid19015485">{{cite journal | vauthors = Sevigny JJ, Ryan JM, van Dyck CH, Peng Y, Lines CR, Nessly ML | title = Growth hormone secretagogue MK-677: no clinical effect on AD progression in a randomized trial |authorlink3 = Christopher H. van Dyck | journal = Neurology | volume = 71 | issue = 21 | pages = 1702–8 | date = November 2008 | pmid = 19015485 | doi = 10.1212/01.wnl.0000335163.88054.e7 }}</ref> Another clinical demonstrated that Cephalon's IGF-1 does not slow the progression of weakness in [[Amyotrophic lateral sclerosis|ALS]] patients, but other studies have shown strong beneficial effects of IGF-1 replacement therapy in ALS patients,<ref name="pmid16197815">{{cite journal | vauthors = Nagano I, Shiote M, Murakami T, Kamada H, Hamakawa Y, Matsubara E, Yokoyama M, Moritaz K, Shoji M, Abe K | title = Beneficial effects of intrathecal IGF-1 administration in patients with amyotrophic lateral sclerosis | journal = Neurol. Res. | volume = 27 | issue = 7 | pages = 768–72 | date = October 2005 | pmid = 16197815 | doi = 10.1179/016164105X39860 }}</ref> and therefore IGF-1 may have the potential to be an effective and safe medicine against ALS,<ref name="pmid18608100">{{cite journal | vauthors = Sakowski SA, Schuyler AD, Feldman EL | title = Insulin-like growth factor-I for the treatment of amyotrophic lateral sclerosis | journal = Amyotroph Lateral Scler | volume = 10 | issue = 2 | pages = 63–73 | date = April 2009 | pmid = 18608100 | pmc = 3211070 | doi = 10.1080/17482960802160370 }}</ref> however other studies had conflicting results.<ref name="pmid19029516">{{cite journal | vauthors = 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 | title = Subcutaneous IGF-1 is not beneficial in 2-year ALS trial | journal = Neurology | volume = 71 | issue = 22 | pages = 1770–5 | date = November 2008 | pmid = 19029516 | pmc = 2617770 | doi = 10.1212/01.wnl.0000335970.78664.36 | laysummary = http://www.newswise.com/articles/view/546591/ | laysource = newswise.com }}</ref>
 
== Society and culture ==
In December 2006 a version of IGF-1 marketed by Insmed was found to infringe on patents licensed by Tercica which also sold a version of IGF-1; Tercica then sought to get a U.S. district court judge to ban sales of Iplex.<ref name="urlNY_Times">{{cite web | url = https://www.nytimes.com/2007/02/17/business/17patent.html?_r=1&ref=health | title = Growth Drug Is Caught Up in Patent Fight | vauthors = Pollack A | date = 17 February 2007 | work = The New York Times | pages =| accessdate = 28 March 2010  }}</ref> To settle patent infringement charges and resolve all litigation between the two companies, in March 2007 Insmed 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 at that time.<ref name="url_NY_Times_2">{{cite web | url = https://www.nytimes.com/2007/03/07/business/07patent.html?ref=health | title = To Settle Suit, Maker Agrees to Withdraw Growth Drug | vauthors = Pollack A | date = 7 March 2007 | work = The New York Times | pages =  | accessdate = 28 March 2010 }}</ref>
 
Numerous sources have claimed that [[Deer Antler Spray]], purportedly extracted from cervid sources, contains IGF-1.<ref name="urlDeer-antler spray: What is IGF-1? - CBS News">{{cite web | url = http://www.cbsnews.com/8301-204_162-57566713/deer-antler-spray-what-is-igf-1/ | title = Deer-antler spray: What is IGF-1? | publisher =  CBS News | date = 30 January 2013 | author = Jaslow R }}</ref><ref>Rovell D (9 August 2011). [https://www.cnbc.com/id/44075592 "Deer Antler Velvet Sales On The Rise, Does It Really Work?"]. CNBC.com</ref><ref>Spector D (05-15-13). "[http://www.businessinsider.com/what-is-deer-antler-spray-2013-5 Deer Antler Spray: The Natural Supplement That Seems Too Good To Be True]". BusinessInsider.com.</ref><ref>Kotz D. (31 January 2013). "[http://www.boston.com/dailydose/2013/01/31/are-deer-antler-spray-and-other-muscle-boosting-supplements-safe/KuuI2uEnrWqKtoaC3JVhYI/story.html Are deer antler spray and other muscle-boosting supplements safe?]". Boston Globe</ref> Credence to this claim comes from the fact that deer's antlers grow extremely rapidly and that the associated cellular factors can similarly aid in skeletal healing in humans. IGF-1 is currently banned by various sporting bodies. However, sprays and pills claiming to be 'deer antler velvet extracts' are freely available on the market.<ref name="urlS.W.A.T.S. salesman says he watched Tide players use deer spray - CBSSports.com">{{cite web | url = http://www.cbssports.com/collegefootball/blog/eye-on-college-football/21623944/swats-salesman-says-he-watched-tide-players-use-deer-spray | title = S.W.A.T.S. salesman says he watched Tide players use deer spray | publisher = CBSSports.com | author = Hinnen J | date = 30 January 2013 }}</ref> As IGF-1 is a protein, it is poorly absorbed orally since it is rapidly [[proteolysis|broken down]] in the [[gastrointestinal tract]]; and large molecular weight and high hydrophilicity prevents it from being absorbed by intestinal tissue.<ref name = "Amet_2010">{{cite book |veditors=Narang AS, Mahato RM | title = Targeted Delivery of Small and Macromolecular Drugs | vauthors = Amet N, Chen X, ((Lee H-F)), Zaro J, ((Shen W-C)) | last-author-amp = yes | chapter = Transferrin Receptor–Mediated Transcytosis in Intestinal Epithelial Cells for Gastrointestinal Absorption of Protein Drugs | year = 2010 | publisher = CRC Press/Taylor & Francis Group | location = Boca Ratan, Florida | isbn = 142008772X | page = 32 }}</ref><ref>{{cite web | url = http://www.pharmtech.com/are-oral-peptide-drugs-horizon | title = Are Oral Peptide Drugs on the Horizon? | last = Hernandez | first = Randi | name-list-format = vanc | work = Pharm Tech | date = July 2016 }}</ref> In September 2013, the headquarters of SWATS, a well-known distributor of deer antler spray and other controversial products, was raided and ordered to shut down by [[Alabama]]'s [[Alabama Attorney General|attorney general]] citing "numerous serious and willful violations of Alabama’s deceptive trade practices act".<ref name="url_whnt.com">{{cite web | url = http://whnt.com/2013/09/05/sports-performance-company-ordered-to-stop-selling-deer-antler-spray-other-products/ | title = Sports Performance Company Ordered to Stop Selling ‘Deer Antler Spray,’ Other Products | publisher = WHNT | author = Galloway D | date = 5 September 2013 }}</ref><ref name="url_si.com">{{cite web | url = http://tracking.si.com/2013/09/05/ray-lewis-deer-antler-office-raided/ | title = Ray Lewis’ alleged deer antler supplier has office raided in Alabama | publisher = SI.com | author = Otano J | date = 5 September 2013 }}</ref> Deer antler spray has been linked to prion disease.<ref>{{cite journal | vauthors = Angers RC, Seward TS, Napier D, Green M, Hoover E, Spraker T, O'Rourke K, Balachandran A, Telling GC | title = Chronic wasting disease prions in elk antler velvet | journal = Emerging Infectious Diseases | volume = 15 | issue = 5 | pages = 696–703 | date = May 2009 | pmid = 19402954 | pmc = 2687044 | doi = 10.3201/eid1505.081458 }}</ref>
 
In 2012, the popular [[BBC Two|BBC2]] television documentary [[Horizon (UK TV series)|Horizon]] episode [[List of Horizon episodes|''Eat, Fast, & Live Longer'']] mentions IGF-1 extensively.<ref>{{Cite web|url=http://www.bbc.co.uk/programmes/b01lxyzc|title=Eat, Fast and Live Longer, 2012-2013, Horizon|website=BBC|access-date=2017-10-20}}</ref>  The documentary suggests that downregulating IGF-1 activity through [[calorie restriction]] or [[intermittent fasting]] can help reduce development of cancer, diabetes, and the general effects of aging.<ref>{{Cite news|url=https://www.theguardian.com/tv-and-radio/2012/aug/06/eat-fast-and-live-longer|title=TV review: Horizon: Eat, Fast and Live Longer; Britain's High Street Gamble|last=Wollaston|first=Sam |name-list-format = vanc |date=2012-08-06|work=The Guardian|access-date=2017-10-20|language=en-GB|issn=0261-3077}}</ref>  While admitting that this was only one data point, with blood tests before and after, host [[Michael Mosley (broadcaster)|Michael Mosley]] was able to reduce his IGF-1 level by half after implementing the [[5:2 diet]] for one month.
 
==See also==
* [[Somatopause]]
 
== References ==
{{reflist|32em}}
 
== External links ==
* {{MeshName|Insulin-Like+Growth+Factor+I}}
* {{MeshName|Insulin-Like+Growth+Factor+I}}
*[http://www.magicfoundation.org/www/docs/978.1035/ IGF-1 for Parents]
* [http://labtestsonline.org/understanding/analytes/igf1/tab/test/ IGF-1] at Lab Tests Online
*[http://www.thesage-speaks.com/igf-1-insulin-like-gowth-factor-explained/ IGF-1 & Bodybuilding]
* [http://www.protean.cz/en/recombinant-proteins/cancer-markers IGF-1] recombinant GFP labeled at [http://protean.cz Protean Ltd.]
*[http://www.magicfoundation.org/www/docs/978.1035/insulin-like-growth-factor-deficiency/  IGF1 Deficiency for Parents a section of The MAGIC Foundation for Children's Growth]


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Insulin-like growth factor 1 (IGF-1), also called somatomedin C, 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 7,649 Daltons.[5]

Synthesis and circulation

See also: Neurobiological effects of physical exercise § IGF-1 signaling

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 signaling 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. IGFBP-1 is regulated by insulin.[medical citation needed]

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.

3-d model of IGF-1

Protein intake increases IGF-1 levels in humans, independent of total calorie consumption.[6] Factors that are known to cause variation in the levels of growth hormone (GH) and IGF-1 in the circulation include: insulin levels, genetic make-up, the time of day, age, sex, exercise status, stress levels, nutrition level and body mass index (BMI), disease state, ethnicity, estrogen status and xenobiotic intake.[7]

Mechanism of action

See also: Hypothalamic–pituitary–somatic axis

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, nerve, skin, hematopoietic, and lung cells. In addition to the insulin-like effects, IGF-1 can also regulate cellular DNA synthesis.[8]

IGF-1 binds to at least two cell surface receptor tyrosine kinases: the IGF-1 receptor (IGF1R), and the insulin receptor. Its primary action is mediated by binding to its specific receptor, IGF1R, which is present on the surface of many cell types in many tissues. Binding to the IGF1R 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 .[9][10] The IGF-1 receptor seems to be the "physiologic" receptor because it binds IGF-1 with significantly higher affinity than insulin receptor does. IGF-1 activates the insulin receptor at approximately 0.1 times 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).[medical citation needed]

Insulin-like growth factor 1 receptor (IGF-1R) and other tyrosine kinase growth factor receptors signal through multiple pathways. A key pathway is regulated by phosphatidylinositol-3 kinase (PI3K) and its downstream partner, the mammalian target of rapamycin (mTOR). Rapamycins complex with FKBPP12 to inhibit the mTORC1 complex. mTORC2 remains unaffected and responds by upregulating Akt, driving signals through the inhibited mTORC1. Phosphorylation of eukaryotic initiation factor 4e (eif-4E) [4EBP] by mTOR inhibits the capacity of 4EBP to inhibit eif-4E and slow metabolism.[medical citation needed]

Insulin-like growth factor 1 has been shown to bind and interact with all seven IGF-1 binding proteins (IGFBPs): IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP6, and IGFBP7.[medical citation needed] Some 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.[medical citation needed]

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-2 receptor" (also called the mannose-6 phosphate receptor). The insulin-like 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.

A splice variant of IGF-1 sharing an identical mature region, but with a different E domain is known as mechano-growth factor (MGF).[11]

Clinical significance

Dwarfism

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 3 SD. 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.

People with Laron syndrome have strikingly low rates of cancer and diabetes.[12]

Acromegaly

Acromegaly is a syndrome that results when the anterior pituitary gland produces excess growth hormone (GH). A number of disorders may increase the pituitary's GH output, although most commonly it involves a tumor called pituitary adenoma, derived from a distinct type of cell (somatotrophs). It leads to anatomical changes and metabolic dysfunction caused by elevated GH and insulin-like growth factor 1 (IGF-1) levels.[13]

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 marked 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

Patients with severe primary insulin-like growth factor-1 deficiency (IGFD), called Laron syndrome, may be treated with either IGF-1 alone or in combination with IGFBP-3.[14] Mecasermin (brand name Increlex) is a synthetic analog of IGF-1 which is approved for the treatment of growth failure.[14] IGF-1 has been manufactured recombinantly on a large scale using both yeast and E. coli.

Research

Aging

Signaling through the insulin/IGF-1-like receptor pathway is a significant contributor to biological aging in many organisms. Cynthia Kenyon showed that mutations in the daf-2 gene double the lifespan of the roundworm, C. elegans.[15][16] Daf-2 encodes the worm's unified insulin/IGF-1-like receptor. Despite the impact of IGF1-like on C. elegans longevity, direct application to mammalian aging is not as clear as mammals lack dauer developmental stages. It is also inconsistent with evidence in humans.[17]

There are mixed reports that IGF-1 signaling modulates the aging process in humans and about whether the direction of its effect is positive or negative.[17]

Neuropathy

Therapeutic administration of neurotrophic proteins (IGF-1) is associated with potential reversal of degeneration of spinal cord motor neuron axons in certain peripheral neuropathies.[18]

Cancer

The IGF signaling pathway has been implicated in some forms of cancer.[19][20] People with Laron syndrome, who express low levels of IGF-1, have a greatly reduced risk of developing cancer.[21] Dietary interventions and modifications shown to downregulate IGF-1 activity, such as vegan diets, have been associated with a lower risk of cancer.[22] However, despite considerable research, perturbations specific to cancer are incompletely delineated[23][24] and clinical drug trials have been unsuccessful.[20][25]

Stroke

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.[26]

Clinical trials

Recombinant protein

Several companies have evaluated IGF-1 in clinical trials for a variety of indications, including type 1 diabetes, type 2 diabetes, amyotrophic lateral sclerosis (ALS aka "Lou Gehrig's Disease"),[27] 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.[medical citation needed] However, the sponsor, Genentech, discontinued the program due to an exacerbation of diabetic retinopathy[28] 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,[medical citation needed] and the product has never been approved by the FDA.

Small molecules that upregulate IGF-1

In a clinical trial of an investigational compound ibutamoren, which raises IGF-1 in patients, did not result in an improvement in patients' Alzheimer's symptoms.[29] Another clinical demonstrated that Cephalon's IGF-1 does not slow the progression of weakness in ALS patients, but other studies have shown strong beneficial effects of IGF-1 replacement therapy in ALS patients,[30] and therefore IGF-1 may have the potential to be an effective and safe medicine against ALS,[31] however other studies had conflicting results.[32]

Society and culture

In December 2006 a version of IGF-1 marketed by Insmed was found to infringe on patents licensed by Tercica which also sold a version of IGF-1; Tercica then sought to get a U.S. district court judge to ban sales of Iplex.[33] To settle patent infringement charges and resolve all litigation between the two companies, in March 2007 Insmed 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 at that time.[34]

Numerous sources have claimed that Deer Antler Spray, purportedly extracted from cervid sources, contains IGF-1.[35][36][37][38] Credence to this claim comes from the fact that deer's antlers grow extremely rapidly and that the associated cellular factors can similarly aid in skeletal healing in humans. IGF-1 is currently banned by various sporting bodies. However, sprays and pills claiming to be 'deer antler velvet extracts' are freely available on the market.[39] As IGF-1 is a protein, it is poorly absorbed orally since it is rapidly broken down in the gastrointestinal tract; and large molecular weight and high hydrophilicity prevents it from being absorbed by intestinal tissue.[40][41] In September 2013, the headquarters of SWATS, a well-known distributor of deer antler spray and other controversial products, was raided and ordered to shut down by Alabama's attorney general citing "numerous serious and willful violations of Alabama’s deceptive trade practices act".[42][43] Deer antler spray has been linked to prion disease.[44]

In 2012, the popular BBC2 television documentary Horizon episode Eat, Fast, & Live Longer mentions IGF-1 extensively.[45] The documentary suggests that downregulating IGF-1 activity through calorie restriction or intermittent fasting can help reduce development of cancer, diabetes, and the general effects of aging.[46] While admitting that this was only one data point, with blood tests before and after, host Michael Mosley was able to reduce his IGF-1 level by half after implementing the 5:2 diet for one month.

See also

References

  1. ↑ Höppener JW, de Pagter-Holthuizen P, Geurts van Kessel AH, Jansen M, Kittur SD, Antonarakis SE, Lips CJ, Sussenbach JS (1985). "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). "Sequence of cDNA encoding human insulin-like growth factor I precursor". Nature. 306 (5943): 609–11. doi:10.1038/306609a0. PMID 6358902.
  3. ↑ Salmon WD, Daughaday WH (1957). "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). "Mecasermin". BioDrugs. 22 (3): 177–88. doi:10.2165/00063030-200822030-00004. PMID 18481900.
  5. ↑ Rinderknecht E, Humbel RE (1978). "The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulin". J Biol Chem. 253 (8): 2769–2776. PMID 632300.
  6. ↑ Levine ME, Suarez JA, Brandhorst S, Balasubramanian P, Cheng CW, Madia F, Fontana L, Mirisola MG, Guevara-Aguirre J, Wan J, Passarino G, Kennedy BK, Wei M, Cohen P, Crimmins EM, Longo VD (2002). "Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population". Cell Metabolism. 19 (3): 407–417. doi:10.1016/j.cmet.2014.02.006. PMC 3988204. PMID 24606898.
  7. ↑ Scarth JP (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. doi:10.1080/00498250600621627. PMID 16702112.
  8. ↑ Yakar S, Rosen CJ, Beamer WG, Ackert-Bicknell CL, Wu Y, Liu JL, Ooi GT, Setser J, Frystyk J, Boisclair YR, LeRoith D (2002). "Circulating levels of IGF-1 directly regulate bone growth and density". Journal of Clinical Investigation. 110 (6): 771–781. doi:10.1172/JCI15463. PMC 151128. PMID 12235108.
  9. ↑ Peruzzi F, Prisco M, Dews M, Salomoni P, Grassilli E, Romano G, Calabretta B, Baserga R (October 1999). "Multiple signaling pathways of the insulin-like growth factor 1 receptor in protection from apoptosis". Molecular and Cellular Biology. 19 (10): 7203–15. doi:10.1128/mcb.19.10.7203. PMC 84713. PMID 10490655.
  10. ↑ Juin P, Hueber AO, Littlewood T, Evan G (June 1999). "c-Myc-induced sensitization to apoptosis is mediated through cytochrome c release". Genes & Development. 13 (11): 1367–81. doi:10.1101/gad.13.11.1367. PMC 316765. PMID 10364155.
  11. ↑ Carpenter V, Matthews K, Devlin G, Stuart S, Jensen J, Conaglen J, Jeanplong F, Goldspink P, Yang SY, Goldspink G, Bass J, McMahon C (February 2008). "Mechano-growth factor reduces loss of cardiac function in acute myocardial infarction". Heart Lung Circ. 17 (1): 33–9. doi:10.1016/j.hlc.2007.04.013. PMID 17581790.
  12. ↑ Wade N (17 February 2011). "Ecuadorean Villagers May Hold Secret to Longevity". New York Times.
  13. ↑ Giustina A, Chanson P, Kleinberg D, Bronstein MD, Clemmons DR, Klibanski A, van der Lely AJ, Strasburger CJ, Lamberts SW, Ho KK, Casanueva FF, Melmed S (2014). "Expert consensus document: A consensus on the medical treatment of acromegaly". Nat Rev Endocrinol. 10 (4): 243–8. doi:10.1038/nrendo.2014.21. PMID 24566817.
  14. ↑ 14.0 14.1 Rosenbloom AL (2007). "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.
  15. ↑ Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R (1993). "A C. elegans mutant that lives twice as long as wild type". Nature. 366 (6454): 461–464. doi:10.1038/366461a0. PMID 8247153.
  16. ↑ Lapierre LR, Hansen M (2012). "Lessons from C. elegans: signaling pathways for longevity". Trends Endocrinol. Metab. 23 (12): 637–44. doi:10.1016/j.tem.2012.07.007. PMC 3502657. PMID 22939742.
  17. ↑ 17.0 17.1 Sattler FR (August 2013). "Growth hormone in the aging male". Best Pract. Res. Clin. Endocrinol. Metab. 27 (4): 541–55. doi:10.1016/j.beem.2013.05.003. PMC 3940699. PMID 24054930.
  18. ↑ Lewis ME, Neff NT, Contreras PC, Stong DB, Oppenheim RW, Grebow PE, Vaught JL (Nov 1993). "Insulin-like growth factor-I: potential for treatment of motor neuronal disorders". Experimental Neurology. 124 (1): 73–88. doi:10.1006/exnr.1993.1177. PMID 8282084.
  19. ↑ Arnaldez FI, Helman LJ (Jun 2012). "Targeting the insulin growth factor receptor 1". Hematology/Oncology Clinics of North America. 26 (3): 527–42, vii–viii. doi:10.1016/j.hoc.2012.01.004. PMC 3334849. PMID 22520978.
  20. ↑ 20.0 20.1 Yang Y, Yee D (Dec 2012). "Targeting insulin and insulin-like growth factor signaling in breast cancer". Journal of Mammary Gland Biology and Neoplasia. 17 (3–4): 251–61. doi:10.1007/s10911-012-9268-y. PMC 3534944. PMID 23054135.
  21. ↑ Gallagher EJ, LeRoith D (April 2011). "Is growth hormone resistance/IGF-1 reduction good for you?". Cell Metab. 13 (4): 355–6. doi:10.1016/j.cmet.2011.03.003. PMID 21459318.
  22. ↑ McCarty MF (1999). "Vegan proteins may reduce risk of cancer, obesity, and cardiovascular disease by promoting increased glucagon activity". Med. Hypotheses. 53 (6): 459–85. doi:10.1054/mehy.1999.0784. PMID 10687887.
  23. ↑ Siddle K (2012). "Molecular basis of signaling specificity of insulin and IGF receptors: neglected corners and recent advances". Frontiers in Endocrinology. 3: 34. doi:10.3389/fendo.2012.00034. PMC 3355962. PMID 22649417.
  24. ↑ Girnita L, Worrall C, Takahashi S, Seregard S, Girnita A (Jul 2014). "Something old, something new and something borrowed: emerging paradigm of insulin-like growth factor type 1 receptor (IGF-1R) signaling regulation". Cellular and Molecular Life Sciences. 71 (13): 2403–27. doi:10.1007/s00018-013-1514-y. PMC 4055838. PMID 24276851.
  25. ↑ Singh P, Alex JM, Bast F (Jan 2014). "Insulin receptor (IR) and insulin-like growth factor receptor 1 (IGF-1R) signaling systems: novel treatment strategies for cancer". Medical Oncology. 31 (1): 805. doi:10.1007/s12032-013-0805-3. PMID 24338270.
  26. ↑ Fletcher L, Kohli S, Sprague SM, Scranton RA, Lipton SA, Parra A, Jimenez DF, Digicaylioglu M (July 2009). "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.
  27. ↑ Vaught JL, Contreras PC, Glicksman MA, Neff NT (1996). "Potential utility of rhIGF-1 in neuromuscular and/or degenerative disease". Ciba Found. Symp. 196: 18–27, discussion 27–38. PMID 8866126.
  28. ↑ "Genentech Discontinues IGF-I Drug Development Effort in Diabetes" (Press release). Genentech. 5 September 1997. Retrieved 15 March 2013.
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  30. ↑ Nagano I, Shiote M, Murakami T, Kamada H, Hamakawa Y, Matsubara E, Yokoyama M, Moritaz K, Shoji M, Abe K (October 2005). "Beneficial effects of intrathecal IGF-1 administration in patients with amyotrophic lateral sclerosis". Neurol. Res. 27 (7): 768–72. doi:10.1179/016164105X39860. PMID 16197815.
  31. ↑ Sakowski SA, Schuyler AD, Feldman EL (April 2009). "Insulin-like growth factor-I for the treatment of amyotrophic lateral sclerosis". Amyotroph Lateral Scler. 10 (2): 63–73. doi:10.1080/17482960802160370. PMC 3211070. PMID 18608100.
  32. ↑ 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). "Subcutaneous IGF-1 is not beneficial in 2-year ALS trial". Neurology. 71 (22): 1770–5. doi:10.1212/01.wnl.0000335970.78664.36. PMC 2617770. PMID 19029516. Lay summary – newswise.com.
  33. ↑ Pollack A (17 February 2007). "Growth Drug Is Caught Up in Patent Fight". The New York Times. Retrieved 28 March 2010.
  34. ↑ Pollack A (7 March 2007). "To Settle Suit, Maker Agrees to Withdraw Growth Drug". The New York Times. Retrieved 28 March 2010.
  35. ↑ Jaslow R (30 January 2013). "Deer-antler spray: What is IGF-1?". CBS News.
  36. ↑ Rovell D (9 August 2011). "Deer Antler Velvet Sales On The Rise, Does It Really Work?". CNBC.com
  37. ↑ Spector D (05-15-13). "Deer Antler Spray: The Natural Supplement That Seems Too Good To Be True". BusinessInsider.com.
  38. ↑ Kotz D. (31 January 2013). "Are deer antler spray and other muscle-boosting supplements safe?". Boston Globe
  39. ↑ Hinnen J (30 January 2013). "S.W.A.T.S. salesman says he watched Tide players use deer spray". CBSSports.com.
  40. ↑ Amet N, Chen X, Lee H-F, Zaro J & Shen W-C (2010). "Transferrin Receptor–Mediated Transcytosis in Intestinal Epithelial Cells for Gastrointestinal Absorption of Protein Drugs". In Narang AS & Mahato RM. Targeted Delivery of Small and Macromolecular Drugs. Boca Ratan, Florida: CRC Press/Taylor & Francis Group. p. 32. ISBN 142008772X.
  41. ↑ Hernandez R (July 2016). "Are Oral Peptide Drugs on the Horizon?". Pharm Tech.
  42. ↑ Galloway D (5 September 2013). "Sports Performance Company Ordered to Stop Selling 'Deer Antler Spray,' Other Products". WHNT.
  43. ↑ Otano J (5 September 2013). "Ray Lewis' alleged deer antler supplier has office raided in Alabama". SI.com.
  44. ↑ Angers RC, Seward TS, Napier D, Green M, Hoover E, Spraker T, O'Rourke K, Balachandran A, Telling GC (May 2009). "Chronic wasting disease prions in elk antler velvet". Emerging Infectious Diseases. 15 (5): 696–703. doi:10.3201/eid1505.081458. PMC 2687044. PMID 19402954.
  45. ↑ "Eat, Fast and Live Longer, 2012-2013, Horizon". BBC. Retrieved 2017-10-20.
  46. ↑ Wollaston S (2012-08-06). "TV review: Horizon: Eat, Fast and Live Longer; Britain's High Street Gamble". The Guardian. ISSN 0261-3077. Retrieved 2017-10-20.

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