Insulin-like growth factor 1

Insulin like growth factor 1

PDB rendering based on 1bqt.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols IGF1 ; IGF-I; IGFI; MGF
External IDs OMIM: 147440 MGI: 96432 HomoloGene: 515 GeneCards: IGF1 Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 3479 16000
Ensembl ENSG00000017427 ENSMUSG00000020053
UniProt P05019 P05017
RefSeq (mRNA) NM_000618 NM_001111274
RefSeq (protein) NP_000609 NP_001104744
Location (UCSC) Chr 12:
102.4 – 102.48 Mb		 Chr 10:
87.86 – 87.94 Mb
PubMed search

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 Dalton.[5]

Synthesis and circulation

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.

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, race, estrogen status and xenobiotic intake.[7]

Mechanism of action

Its primary action is mediated by binding to its specific receptor, the insulin-like growth factor 1 receptor (IGF1R), which is present on many cell types in many tissues. Binding to the IGF1R, a receptor tyrosine kinase, 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 . IGF-1 binds to at least two cell surface receptors: the IGF-1 receptor (IGF1R), and the insulin receptor. The IGF-1 receptor seems to be the "physiologic" receptor – it binds IGF-1 at significantly higher affinity than the IGF-1 that 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 0.1 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).

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, nerves, skin, hematopoietic cell, 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.[8]


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.

Insulin-like growth factor 1 has been shown to bind and interact with all the IGF-1 binding proteins (IGFBPs), of which there are seven: IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP6, and IGFBP7. 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.

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).[9]

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.[10]

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.[11]

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) may be treated with either IGF-1 alone or in combination with IGFBP-3.[12] Mecasermin (brand name Increlex) is a synthetic analog of IGF-1 which is approved for the treatment of growth failure.[12] 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.[13][14] 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.[15]

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.[15]

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.[16]

Cancer

The IGF signaling pathway is implicated in some cancers.[17][18] People with Laron syndrome have a lessened risk of developing cancer.[19] Dietary interventions and modifications such as vegan diets shown to downregulate IGF-1 activity, has been associated with lower risk of cancer.[20] However, despite considerable research, perturbations specific to cancer are incompletely delineated[21][22] and clinical drug trials have been unsuccessful.[18][23]

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.[24]

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"),[25] 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[26] 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.

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.[27] Another clinical demonstrated that Cephalon's IGF-1 does not slow the progression of weakness in ALS patients, but other studies shown strong beneficial effects of IGF-1 replacement therapy in ALS patients,[28] and therefore IGF-1 may have the potential to be an effective and safe medicine against ALS,[29] however other studies had conflicting results.[30]

Society and culture

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.[31] 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.[32]

Numerous sources have claimed that Deer Antler Spray, purportedly extracted from cervid sources, contains IGF-1.[33][34][35][36] 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.[37] As IGF-1 is a protein, it cannot be absorbed orally since it is rapidly broken down in the gastrointestinal tract.[38] In September 2013, the headquarters of SWATS, an infamous 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".[39][40]

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. ↑ 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.
  10. ↑ Wade N (17 February 2011). "Ecuadorean Villagers May Hold Secret to Longevity". New York Times.
  11. ↑ 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.
  12. 1 2 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.
  13. ↑ 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.
  14. ↑ 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.
  15. 1 2 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. PMID 24054930.
  16. ↑ 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.
  17. ↑ 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.
  18. 1 2 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ "Genentech Discontinues IGF-I Drug Development Effort in Diabetes" (Press release). Genentech. 5 September 1997. Retrieved 15 March 2013.
  27. ↑ Sevigny JJ, Ryan JM, van Dyck CH, Peng Y, Lines CR, Nessly ML (November 2008). "Growth hormone secretagogue MK-677: no clinical effect on AD progression in a randomized trial". Neurology 71 (21): 1702–8. doi:10.1212/01.wnl.0000335163.88054.e7. PMID 19015485.
  28. ↑ 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.
  29. ↑ 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.
  30. ↑ 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.
  31. ↑ Pollack A (17 February 2007). "Growth Drug Is Caught Up in Patent Fight". The New York Times. Retrieved 28 March 2010.
  32. ↑ Pollack A. (7 March 2007). "To Settle Suit, Maker Agrees to Withdraw Growth Drug". The New York Times. Retrieved 28 March 2010.
  33. ↑ Jaslow R (30 January 2013). "Deer-antler spray: What is IGF-1?". CBS News.
  34. ↑ Rovell D (9 August 2011). "Deer Antler Velvet Sales On The Rise, Does It Really Work?". CNBC.com
  35. ↑ Spector D (05-15-13). "Deer Antler Spray: The Natural Supplement That Seems Too Good To Be True". BusinessInsider.com.
  36. ↑ Kotz D. (31 January 2013). "Are deer antler spray and other muscle-boosting supplements safe?". Boston Globe
  37. ↑ Hinnen J (30 January 2013). "S.W.A.T.S. salesman says he watched Tide players use deer spray". CBSSports.com.
  38. ↑ Amet N, ChenX , Lee H-F, Zaro J, and 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.
  39. ↑ Galloway D (5 September 2013). "Sports Performance Company Ordered to Stop Selling ‘Deer Antler Spray,’ Other Products". WHNT.
  40. ↑ Otano J (5 September 2013). "Ray Lewis’ alleged deer antler supplier has office raided in Alabama". SI.com.

Further reading

  • Butler AA, Yakar S, LeRoith D (2002). "Insulin-like growth factor-I: compartmentalization within the somatotropic axis?". News Physiol. Sci. 17: 82–5. PMID 11909998. 
  • Maccario M, Tassone F, Grottoli S, Rossetto R, Gauna C, Ghigo E (2002). "Neuroendocrine and metabolic determinants of the adaptation of GH/IGF-I axis to obesity". Ann. Endocrinol. (Paris) 63 (2 Pt 1): 140–4. PMID 11994678. 
  • Camacho-Hübner C, Woods KA, Clark AJ, Savage MO (2003). "Insulin-like growth factor (IGF)-I gene deletion". Reviews in endocrine & metabolic disorders 3 (4): 357–61. doi:10.1023/A:1020957809082. PMID 12424437. 
  • Dantzer B, Swanson EM (2012). "Mediation of vertebrate life histories via insulin-like growth factor-1". Biological Reviews 87 (2): 414–429. doi:10.1111/j.1469-185X.2011.00204.x. PMID 21981025. 
  • Trojan LA, Kopinski P, Wei MX, Ly A, Glogowska A, Czarny J, Shevelev A, Przewlocki R, Henin D, Trojan J (2004). "IGF-I: from diagnostic to triple-helix gene therapy of solid tumors". Acta Biochim. Pol. 49 (4): 979–90. PMID 12545204. 
  • Winn N, Paul A, Musaró A, Rosenthal N (2003). "Insulin-like growth factor isoforms in skeletal muscle aging, regeneration, and disease". Cold Spring Harb. Symp. Quant. Biol. 67: 507–18. doi:10.1101/sqb.2002.67.507. PMID 12858577. 
  • Delafontaine P, Song YH, Li Y (2005). "Expression, regulation, and function of IGF-1, IGF-1R, and IGF-1 binding proteins in blood vessels". Arterioscler. Thromb. Vasc. Biol. 24 (3): 435–44. doi:10.1161/01.ATV.0000105902.89459.09. PMID 14604834. 
  • Trejo JL, Carro E, Garcia-Galloway E, Torres-Aleman I (2004). "Role of insulin-like growth factor I signaling in neurodegenerative diseases". J. Mol. Med. 82 (3): 156–62. doi:10.1007/s00109-003-0499-7. PMID 14647921. 
  • Rabinovsky ED (2004). "The multifunctional role of IGF-1 in peripheral nerve regeneration". Neurol. Res. 26 (2): 204–10. doi:10.1179/016164104225013851. PMID 15072640. 
  • Rincon M, Muzumdar R, Atzmon G, Barzilai N (2005). "The paradox of the insulin/IGF-1 signaling pathway in longevity". Mech. Ageing Dev. 125 (6): 397–403. doi:10.1016/j.mad.2004.03.006. PMID 15272501. 
  • Conti E, Carrozza C, Capoluongo E, Volpe M, Crea F, Zuppi C, Andreotti F (2005). "Insulin-like growth factor-1 as a vascular protective factor". Circulation 110 (15): 2260–5. doi:10.1161/01.CIR.0000144309.87183.FB. PMID 15477425. 
  • Wood AW, Duan C, Bern HA (2005). "Insulin-like growth factor signaling in fish". Int. Rev. Cytol. International Review of Cytology 243: 215–85. doi:10.1016/S0074-7696(05)43004-1. ISBN 9780123646477. PMID 15797461. 
  • Sandhu MS (2005). "Insulin-like growth factor-I and risk of type 2 diabetes and coronary heart disease: molecular epidemiology". Endocrine development. Endocrine Development 9: 44–54. doi:10.1159/000085755. ISBN 3-8055-7926-8. PMID 15879687. 
  • Ye P, D'Ercole AJ (2006). "Insulin-like growth factor actions during development of neural stem cells and progenitors in the central nervous system". J. Neurosci. Res. 83 (1): 1–6. doi:10.1002/jnr.20688. PMID 16294334. 
  • Gómez JM (2006). "The role of insulin-like growth factor I components in the regulation of vitamin D". Current pharmaceutical biotechnology 7 (2): 125–32. doi:10.2174/138920106776597621. PMID 16724947. 
  • Federico G, Street ME, Maghnie M, Caruso-Nicoletti M, Loche S, Bertelloni S, Cianfarani S (2006). "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)". J. Endocrinol. Invest. 29 (8): 732–7. doi:10.1007/bf03344184. PMID 17033263. 
  • Zakula Z, Koricanac G, Putnikovic B, Markovic L, Isenovic ER (2007). "Regulation of the inducible nitric oxide synthase and sodium pump in type 1 diabetes". Med. Hypotheses 69 (2): 302–6. doi:10.1016/j.mehy.2006.11.045. PMID 17289286. 
  • Trojan J, Cloix JF, Ardourel MY, Chatel M, Anthony DD (2007). "Insulin-like growth factor type I biology and targeting in malignant gliomas". Neuroscience 145 (3): 795–811. doi:10.1016/j.neuroscience.2007.01.021. PMID 17320297. 
  • Venkatasubramanian G, Chittiprol S, Neelakantachar N, Naveen MN, Thirthall J, Gangadhar BN, Shetty KT (October 2007). "Insulin and insulin-like growth factor-1 abnormalities in antipsychotic-naive schizophrenia". Am J Psychiatry 164 (10): 1557–60. doi:10.1176/appi.ajp.2007.07020233. PMID 17898347. 

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