Insulin-like growth factor 1
|Insulin-like growth factor 1 (somatomedin C)|
PDB rendering based on 1bqt.
|RNA expression pattern|
Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a protein that in humans is encoded by the IGF1 gene. IGF-1 has also been referred to as a "sulfation factor" 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.
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.
- 1 Synthesis and circulation
- 2 Mechanism of action
- 3 Receptors
- 4 Related growth factors
- 5 Factors influencing the levels in the circulation
- 6 Clinical significance
- 7 Diagnostic test
- 8 As a therapeutic agent
- 9 Miscellaneous uses
- 10 Interactions
- 11 References
- 12 Further reading
- 13 External links
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 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.
Mechanism of action
Its primary action is mediated by binding to its specific receptor, the Insulin-like growth factor 1 receptor, abbreviated as ""IGF1R"", 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 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.
Deficiency of either growth hormone or IGF-1 therefore results in diminished stature. GH-deficient children are given recombinant GH to increase their size. IGF-1 deficient humans, who are categorized as having Laron syndrome, or Laron's dwarfism, are treated with recombinant IGF-1. In beef cattle, circulating IGF-1 concentrations are related to reproductive performance.
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.W
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 0.1x 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.
Other 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.
Factors influencing the levels in the circulation
Factors that are known to cause variation in the levels of growth hormone (GH) and IGF-1 in the circulation include: 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. 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. In free-ranging animals, nutrition and predators may influences levels of IGF-1.
Contribution to aging
It is now widely accepted that signaling through the insulin/IGF-1-like receptor pathway is a significant contributor to the biological aging process in many organisms. This avenue of research first achieved prominence with the work of Cynthia Kenyon, who showed that mutations in the daf-2 gene double the lifespan of the roundworm, C. elegans. 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 do not form dauer like developmental stages.
Insulin/IGF-1-like signaling is conserved from worms to humans. In vitro experiments show that mutations that reduce insulin/IGF-1 signaling have been shown to decelerate the degenerative aging process and extend lifespan in a wide range of organisms, including Drosophila melanogaster, mice, and possibly humans. Reduced IGF-1 signaling is also thought to contribute to the "anti-aging" effects of Calorie restriction.
Nevertheless the situation in vivo is evidently different. Anabolic deficiency in men with chronic heart failure is prevalent and could have an associated detrimental impact on survival. Deficiency of anabolic hormones identifies groups with a higher mortality.
Therapeutic administration with neurotrophic proteins (IGF I) is associated with potential reversal of degeneration of spinal cord motor neuron axons in certain peripheral neuropathies.
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 has a pathogenic role in cancer. Studies have shown that increased levels of IGF lead to increased growth of existing cancer cells. People with Laron syndrome have also recently been shown to be of much less risk to develop cancer.
|Reference ranges for IGF-1
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 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
Mecasermin (brand name Increlex) is a synthetic analog of IGF-1 which is approved for the treatment of growth failure. 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 additional indications, including 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.
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. 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.
By delivering Iplex in a complex, patients might get the same efficacy with regard to growth rates but experience fewer side effects with less severe hypoglycemia. This medication might emulate IGF-1's endogenous complexing, as 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.
IGFBP-3 is a carrier for IGF-1, meaning that IGF-1 binds IGFBP-3, creating a complex whose combined molecular weight and binding affinity allows the growth factor to have an increased half-life in serum. Without binding to IGFBP-3, IGF-1 is cleared rapidly through the kidney, due to its low molecular weight. But when bound to IGFBP-3, IGF-1 evades renal clearance. Also, since IGFBP-3 has a lower affinity for IGF-1 than IGF-1 has for its receptor, IGFR, its binding does not interfere with IGF-1 function.
In a clinical trial of an investigational compound MK-677, which raises IGF-1 in patients, did not result in an improvement in patients' Alzheimer's symptoms. 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-I replacement therapy in ALS patients, and therefore IGF-I may have the potential to be an effective and safe medicine against ALS, however other studies had conflicting results.
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.
Numerous sources have claimed that Deer Antler Spray, purportedly extracted from cervid sources, contains IGF-1. 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. As IGF-1 is a protein, it cannot be absorbed orally since it is rapidly broken down in the gastrointestinal tract. 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".
Insulin-like growth factor 1 has been shown to bind and interact with all the IGF-1 Binding Proteins (IGFBPs), of which there are six (IGFBP1–6).
- 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.
- 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.
- Salmon W, Daughaday W (1957). "A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro". J Lab Clin Med 49 (6): 825–36. PMID 13429201.
- Keating GM (2008). "Mecasermin". BioDrugs 22 (3): 177–88. doi:10.2165/00063030-200822030-00004. PMID 18481900.
- Miura, Y.; Kato, H.; Noguchi, T. (2007). "Effect of dietary proteins on insulin-like growth factor-1 (IGF-1) messenger ribonucleic acid content in rat liver". British Journal of Nutrition 67 (2): 257. doi:10.1079/BJN19920029. PMID 1596498.
- Cheung SC, Liu LZ, Lan LL, Liu QQ, Sun SS, Chan JC, Tong PC (2011). "Glucose lowering effect of transgenic human insulin-like growth factor-I from rice: in vitro and in vivo studies". BMC Biotechnol. 11: 37. doi:10.1186/1472-6750-11-37. PMC 3098155. PMID 21486461.
- Yilmaz A, Davis ME, RCM Simmen RCM (1999). "Reproductive performance of bulls divergently selected on the basis of blood serum insulin-like growth factor I concentration". J Anim Sci 77 (4): 835–9. PMID 10328346.
- 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.
- Scarth J (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.
- "The power of intermittent fasting". BBC News. Retrieved 2 May 2013.
- See publications documenting series of experiments at Cynthia Kenyon lab, in particular, Dorman JB, Albinder B, Shroyer T, Kenyon C (December 1995). "The Age-1 and Daf-2 Genes Function in a Common Pathway to Control the Lifespan of Caenorhabditis Elegans". Genetics 141 (4): 1399–406. PMC 1206875. PMID 8601482.; and Apfeld J, Kenyon C (October 1998). "Cell nonautonomy of C. elegans daf-2 function in the regulation of diapause and life span". Cell 95 (2): 199–210. doi:10.1016/S0092-8674(00)81751-1. PMID 9790527.
- Bartke A (January 2011). "Single-gene mutations and healthy ageing in mammals". Philos. Trans. R. Soc. Lond., B, Biol. Sci. 366 (1561): 28–34. doi:10.1098/rstb.2010.0281. PMC 3001310. PMID 21115527.
- Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, Wei M, Madia F, Cheng CW, Hwang D, Martin-Montalvo A, Saavedra J, Ingles S, de Cabo R, Cohen P, Longo VD (February 2011). "Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans". Sci Transl Med 3 (70): 70ra13. doi:10.1126/scitranslmed.3001845. PMC 3357623. PMID 21325617.
- Pawlikowska L, Hu D, Huntsman S, Sung A, Chu C, Chen J, Joyner AH, Schork NJ, Hsueh WC, Reiner AP, Psaty BM, Atzmon G, Barzilai N, Cummings SR, Browner WS, Kwok PY, Ziv E (August 2009). "Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity". Aging Cell 8 (4): 460–72. doi:10.1111/j.1474-9726.2009.00493.x. PMC 3652804. PMID 19489743.
- Suh Y, Atzmon G, Cho MO, Hwang D, Liu B, Leahy DJ, Barzilai N, Cohen P (March 2008). "Functionally significant insulin-like growth factor I receptor mutations in centenarians". Proc. Natl. Acad. Sci. U.S.A. 105 (9): 3438–42. doi:10.1073/pnas.0705467105. PMC 2265137. PMID 18316725.
- van Heemst D, Beekman M, Mooijaart SP, Heijmans BT, Brandt BW, Zwaan BJ, Slagboom PE, Westendorp RG (April 2005). "Reduced insulin/IGF-1 signalling and human longevity". Aging Cell 4 (2): 79–85. doi:10.1111/j.1474-9728.2005.00148.x. PMID 15771611.
- Barzilai N, Bartke A (February 2009). "Biological approaches to mechanistically understand the healthy life span extension achieved by calorie restriction and modulation of hormones". J. Gerontol. A Biol. Sci. Med. Sci. 64 (2): 187–91. doi:10.1093/gerona/gln061. PMC 2655014. PMID 19228789.
- Friedrich N, Schneider HJ, Haring R, Nauck M, Völzke H, Kroemer HK, Dörr M, Klotsche J, Jung-Sievers C, Pittrow D, Lehnert H, März W, Pieper L, Wittchen HU, Wallaschofski H, Stalla GK (January 2012). "Improved prediction of all-cause mortality by a combination of serum total testosterone and insulin-like growth factor I in adult men". Steroids 77 (1–2): 52–8. doi:10.1016/j.steroids.2011.10.005. PMID 22037276.
- Jankowska EA, Biel B, Majda J, Szklarska A, Lopuszanska M, Medras M, Anker SD, Banasiak W, Poole-Wilson PA, Ponikowski P (October 2006). "Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival". Circulation 114 (17): 1829–37. doi:10.1161/CIRCULATIONAHA.106.649426. PMID 17030678.
- Insulin-like growth factor-I: potential for treatment of motor neuronal disorders. Lewis ME, Neff NT, Contreras PC, Stong DB, Oppenheim RW, Grebow PE, Vaught JL.SourceCephalon, Inc., West Chester, Pennsylvania 19380!
- Wade N (2011-02-17). "Ecuadorean Villagers May Hold Secret to Longevity". New York Times.
- Arnaldez FI, Helman LJ (June 2012). "Targeting the insulin growth factor receptor 1". Hematol. Oncol. Clin. North Am. 26 (3): 527–42, vii–viii. doi:10.1016/j.hoc.2012.01.004. PMC 3334849. PMID 22520978.
- 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.
- Ranges estimated from quantile regression as shown in table 4 in: Friedrich N, Alte D, Völzke H, Spilcke-Liss E, Lüdemann J, Lerch MM, Kohlmann T, Nauck M, Wallaschofski H (June 2008). "Reference ranges of serum IGF-1 and IGFBP-3 levels in a general adult population: results of the Study of Health in Pomerania (SHIP)". Growth Horm. IGF Res. 18 (3): 228–37. doi:10.1016/j.ghir.2007.09.005. PMID 17997337.
- Rosenbloom AL (August 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.
- 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.
- "Genentech Discontinues IGF-I Drug Development Effort in Diabetes" (Press release). Genentech. 5 September 1997. Retrieved 15 March 2013.
- Pollack A (2007-02-17). "Growth Drug Is Caught Up in Patent Fight". The New York Times. Retrieved 2010-03-28.
- Pollack A. (2007-03-07). "To Settle Suit, Maker Agrees to Withdraw Growth Drug". The New York Times. Retrieved 2010-03-28.
- 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.
- 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.
- 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.
- 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.
- 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.
- Jaslow R (2013-01-30). "Deer-antler spray: What is IGF-1?". CBS News.
- Rovell D (2011-08-09). "Deer Antler Velvet Sales On The Rise, Does It Really Work?". CNBC.com
- Spector D (05-15-13). "Deer Antler Spray: The Natural Supplement That Seems Too Good To Be True". BusinessInsider.com.
- Kotz D. (2013-01-31). "Are deer antler spray and other muscle-boosting supplements safe?". Boston Globe
- Hinnen J (2013-01-30). "S.W.A.T.S. salesman says he watched Tide players use deer spray". CBSSports.com.
- 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.
- Galloway D (2013-09-05). "Sports Performance Company Ordered to Stop Selling ‘Deer Antler Spray,’ Other Products". WHNT.
- Otano J (2013-09-05). "Ray Lewis’ alleged deer antler supplier has office raided in Alabama". SI.com.
- Horton JK, Thimmaiah KN, Houghton JA, Horowitz ME, Houghton PJ (June 1989). "Modulation by verapamil of vincristine pharmacokinetics and toxicity in mice bearing human tumor xenografts". Biochem. Pharmacol. 38 (11): 1727–36. doi:10.1016/0006-2952(89)90405-X. PMID 2735930.
- Ueki I, Ooi GT, Tremblay ML, Hurst KR, Bach LA, Boisclair YR (June 2000). "Inactivation of the acid labile subunit gene in mice results in mild retardation of postnatal growth despite profound disruptions in the circulating insulin-like growth factor system". Proc. Natl. Acad. Sci. U.S.A. 97 (12): 6868–73. doi:10.1073/pnas.120172697. PMC 18767. PMID 10823924.
- Buckway CK, Wilson EM, Ahlsén M, Bang P, Oh Y, Rosenfeld RG (October 2001). "Mutation of three critical amino acids of the N-terminal domain of IGF-binding protein-3 essential for high affinity IGF binding". J. Clin. Endocrinol. Metab. 86 (10): 4943–50. doi:10.1210/jc.86.10.4943. PMID 11600567.
- Cohen P, Graves HC, Peehl DM, Kamarei M, Giudice LC, Rosenfeld RG (October 1992). "Prostate-specific antigen (PSA) is an insulin-like growth factor binding protein-3 protease found in seminal plasma". J. Clin. Endocrinol. Metab. 75 (4): 1046–53. doi:10.1210/jc.75.4.1046. PMID 1383255.
- Twigg SM, Baxter RC (March 1998). "Insulin-like growth factor (IGF)-binding protein 5 forms an alternative ternary complex with IGFs and the acid-labile subunit". J. Biol. Chem. 273 (11): 6074–9. doi:10.1074/jbc.273.11.6074. PMID 9497324.
- Firth SM, Ganeshprasad U, Baxter RC (January 1998). "Structural determinants of ligand and cell surface binding of insulin-like growth factor-binding protein-3". J. Biol. Chem. 273 (5): 2631–8. doi:10.1074/jbc.273.5.2631. PMID 9446566.
- Bach LA, Hsieh S, Sakano K, Fujiwara H, Perdue JF, Rechler MM (May 1993). "Binding of mutants of human insulin-like growth factor II to insulin-like growth factor binding proteins 1-6". J. Biol. Chem. 268 (13): 9246–54. PMID 7683646.
- Qin X, Strong DD, Baylink DJ, Mohan S (September 1998). "Structure-function analysis of the human insulin-like growth factor binding protein-4". J. Biol. Chem. 273 (36): 23509–16. doi:10.1074/jbc.273.36.23509. PMID 9722589.
- Ahmed S, Yamamoto K, Sato Y, Ogawa T, Herrmann A, Higashi S, Miyazaki K (October 2003). "Proteolytic processing of IGFBP-related protein-1 (TAF/angiomodulin/mac25) modulates its biological activity". Biochem. Biophys. Res. Commun. 310 (2): 612–8. doi:10.1016/j.bbrc.2003.09.058. PMID 14521955.
- Oh Y, Nagalla SR, Yamanaka Y, Kim HS, Wilson E, Rosenfeld RG (November 1996). "Synthesis and characterization of insulin-like growth factor-binding protein (IGFBP)-7. Recombinant human mac25 protein specifically binds IGF-I and -II". J. Biol. Chem. 271 (48): 30322–5. doi:10.1074/jbc.271.48.30322. PMID 8939990.
- 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, et al. (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, et al. (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, et al. (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, et al. (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. PMID 17033263.
- Zakula Z, Koricanac G, Putnikovic B, et al. (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, et al. (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.