Biology:Insulin-like growth factor 1

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in molecular structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults.

IGF-1 is a protein that in humans is encoded by the IGF1 gene.[1][2] 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.[3] In dogs, an ancient mutation in IGF1 is the primary cause of the toy phenotype.[4]

IGF-1 is produced primarily by the liver. Production is stimulated by growth hormone (GH). Most of IGF-1 is bound to one of 6 binding proteins (IGF-BP). 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.[5] The lowest levels occur in infancy and old age.[6][7]

A synthetic analog of IGF-1, mecasermin, is used in children for the treatment of growth failure.[8]

Cyclic glycine-proline (cGP) is a metabolite of hormone insulin-like growth factor-1 (IGF-1). It has a cyclic structure, lipophilic nature, and is enzymatically stable which makes it a more favourable candidate for manipulating the binding-release process between IGF-1 and its binding protein, thereby normalising IGF-1 function.

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,[5] 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.[9]

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.[10]

3-d model of IGF-1

Protein intake increases IGF-1 levels in humans, independent of total calorie consumption.[11] Factors that are known to cause a 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.[12]

Mechanism of action

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.[13]

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 .[14][15] 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).

IGF-1 binds and activates its own receptor, IGF-1R, through the cell surface expression of Receptor Tyrosine Kinase's (RTK's)[16] and further signal through multiple intracellular transduction cascades. IGF-1R is the critical role-playing inducer in modulating the metabolic effects of IGF-1 for cellular senescence and survival. At a localized target cell, IGF-1R elicits the mediation of paracrine activity. After its activation the initiation of intracellular signaling occurs inducing a magnitude of signaling pathways. An important mechanistic pathway involved in mediating a cascade affect a key pathway regulated by phosphatidylinositol-3 kinase (PI3K) and its downstream partner, mTOR (mammalian Target of Rapamycin).[16] Rapamycin binds with the enzyme FKBPP12 to inhibit the mTORC1 complex. mTORC2 remains unaffected and responds by up-regulating AKT, driving signals through the inhibited mTORC1. Phosphorylation of Eukaryotic translation initiation factor 4E (EIF4E) by mTOR suppresses the capacity of Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1) to inhibit EIF4E and slow metabolism.[17] A mutation in the signaling pathway PI3K-AKT-mTOR is a big factor in the formation of tumors found predominantly on skin, internal organs, and secondary lymph nodes (Kaposi sarcoma).[18] IGF-1R allows the activation of these signaling pathways and subsequently regulates the cellular longevity and metabolic re-uptake of biogenic substances. A therapeutic approach targeting towards the reduction of such tumor collections could be induced by ganitumab. Ganitumab is a monoclonal antibody (mAb) directed antagonistically against IGF-1R. Ganitumab binds to IGF-1R, preventing binding of IGF-1 and the subsequent triggering of the PI3K-mTOR signaling pathway; inhibition of this pro-survival pathway may result in the inhibition of tumor cell expansion and the induction of tumor cell apoptosis.[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. 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.

Metabolic effects

As a major growth factor, IGF-1 is responsible for stimulating growth of all cell types including cancer cells and causing significant metabolic effects.[19] One important metabolic effect of IGF-1 is its ability to signal cells that sufficient nutrients are available for cells to undergo hypertrophy and cell division.[20] These signals also enable IGF-1 to inhibit cell apoptosis and increase the production of cellular proteins.[20] IGF-1 receptors are ubiquitous, which allows for metabolic changes caused by IGF-1 to occur in all cell types.[19] IGF-1's metabolic effects are far-reaching and can coordinate protein, carbohydrate, and fat metabolism in a variety of different cell types.[19] The regulation of IGF-1's metabolic effects on target tissues is also coordinated with other hormones such as growth hormone and insulin.[21]

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).[22]

Disorders

Laron dwarfism

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.[23] Mecasermin (brand name Increlex) is a synthetic analog of IGF-1 which is approved for the treatment of growth failure.[23]

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 very low rates of cancer and diabetes.[24] Notably people with untreated Laron syndrome also never develop acne.[25]

Acromegaly

Acromegaly is a syndrome that results in the anterior pituitary gland producing 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 both an elevated GH and elevated IGF-1 levels.[26] High level of IGF-1 in acromegaly is related to an increased risk of some cancers, particularly colon cancer and thyroid cancer.[27]

Cancer

A mutation in the signalling pathway PI3K-AKT-mTOR is a factor in the formation of tumors found predominantly on skin, internal organs, and secondary lymph nodes (Kaposi sarcoma).[18]

Use as a diagnostic test

IGF-1 levels can be measured in the blood in 10-1000 ng/ml amounts.[28] 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 measurement over time is often useful for the management of several types of pituitary disease, undernutrition, and growth problems.

Causes of elevated IGF-1 levels

Health effects

Cancer

It has been suggested that consumption of IGF-1 in dairy products could increase cancer risk, particularly prostate cancer.[34][35] However, a 2018 review by the Committee on Carcinogenicity of Chemicals in Food, Consumer Products and the Environment (COC) concluded that there is "insufficient evidence to draw any firm conclusions as to whether exposure to dietary IGF-1 is associated with an increased incidence of cancer in consumers".[35] Certain dairy processes such as fermentation are known to significantly decrease IGF-1 concentrations.[36]

Mortality

A 2022 review found that both high and low levels of IGF‐1 increase mortality risk, whilst a mid‐range (120–160 ng/ml) is associated with the lowest mortality.[37]

Other

Increased IGF-1 levels are associated with a lower risk of cardiovascular disease and ischaemic stroke.[38][39][40]

Clinical trials

Recombinant protein

Several companies have evaluated administering recombinant IGF-1 in clinical trials for type 1 diabetes, type 2 diabetes, amyotrophic lateral sclerosis,[41] severe burn injury and myotonic muscular dystrophy.

Results of clinical trials evaluating the efficacy of IGF-1 in type 1 diabetes and type 2 diabetes showed reduction in hemoglobin A1C levels and daily insulin consumption. However the sponsor discontinued the program due to an exacerbation of diabetic retinopathy,[42] coupled with a shift in corporate focus towards oncology.

Two clinical studies of IGF-1 for ALS were conducted and although one study demonstrated efficacy the second was equivocal, and the product was not submitted for approval to the FDA.

History of name

In the 1950s IGF-1 was called "sulfation factor" because it stimulated sulfation of cartilage in vitro,[43] and in the 1970s due to its effects it was termed "nonsuppressible insulin-like activity" (NSILA).

See also

  • Somatopause

References

  1. ↑ "The human gene encoding insulin-like growth factor I is located on chromosome 12". Human Genetics 69 (2): 157–160. 1985. doi:10.1007/BF00293288. PMID 2982726. 
  2. ↑ "Sequence of cDNA encoding human insulin-like growth factor I precursor". Nature 306 (5943): 609–611. 1983. doi:10.1038/306609a0. PMID 6358902. Bibcode: 1983Natur.306..609J. 
  3. ↑ "The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulin". The Journal of Biological Chemistry 253 (8): 2769–2776. April 1978. doi:10.1016/S0021-9258(17)40889-1. PMID 632300. 
  4. ↑ "Big dog, little dog: mutation explains range of canine sizes". Nature 602 (7895): 18. February 2022. doi:10.1038/d41586-022-00209-0. PMID 35087254. Bibcode: 2022Natur.602...18C. 
  5. ↑ 5.0 5.1 "IGF-1 Induces GHRH Neuronal Axon Elongation during Early Postnatal Life in Mice". PLOS ONE 12 (1): e0170083. 2017. doi:10.1371/journal.pone.0170083. PMID 28076448. Bibcode: 2017PLoSO..1270083D. 
  6. ↑ "Serum insulin-like growth factor I (somatomedin-C) level in normal subjects from infancy to adulthood, pituitary dwarfs and normal variant short children". Endocrinologia Japonica 35 (6): 857–864. December 1988. doi:10.1507/endocrj1954.35.857. PMID 3250861. 
  7. ↑ "Serum insulin-like growth factor I in a random population sample of men and women: relation to age, sex, smoking habits, coffee consumption and physical activity, blood pressure and concentrations of plasma lipids, fibrinogen, parathyroid hormone and osteocalcin". Clinical Endocrinology 41 (3): 351–357. September 1994. doi:10.1111/j.1365-2265.1994.tb02556.x. PMID 7955442. 
  8. ↑ "Mecasermin". BioDrugs 22 (3): 177–188. 2008. doi:10.2165/00063030-200822030-00004. PMID 18481900. 
  9. ↑ "Negative cooperativity in the insulin-like growth factor-I receptor and a chimeric IGF-I/insulin receptor". Endocrinology 135 (1): 472–475. July 1994. doi:10.1210/endo.135.1.8013387. PMID 8013387. 
  10. ↑ "Advances in pubertal growth and factors influencing it: Can we increase pubertal growth?". Indian Journal of Endocrinology and Metabolism 18 (Suppl 1): S53–S62. November 2014. doi:10.4103/2230-8210.145075. PMID 25538878. 
  11. ↑ "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. March 2014. doi:10.1016/j.cmet.2014.02.006. PMID 24606898. 
  12. ↑ "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; the Fate of Foreign Compounds in Biological Systems 36 (2–3): 119–218. 2006. doi:10.1080/00498250600621627. PMID 16702112. 
  13. ↑ "Circulating levels of IGF-1 directly regulate bone growth and density". The Journal of Clinical Investigation 110 (6): 771–781. September 2002. doi:10.1172/JCI15463. PMID 12235108. 
  14. ↑ "Multiple signaling pathways of the insulin-like growth factor 1 receptor in protection from apoptosis". Molecular and Cellular Biology 19 (10): 7203–7215. October 1999. doi:10.1128/mcb.19.10.7203. PMID 10490655. 
  15. ↑ "c-Myc-induced sensitization to apoptosis is mediated through cytochrome c release". Genes & Development 13 (11): 1367–1381. June 1999. doi:10.1101/gad.13.11.1367. PMID 10364155. 
  16. ↑ 16.0 16.1 "Insulin-like growth factor 1 (IGF-1): a growth hormone". Molecular Pathology 54 (5): 311–316. October 2001. doi:10.1136/mp.54.5.311. PMID 11577173. 
  17. ↑ "Accumulation of dephosphorylated 4EBP after mTOR inhibition with rapamycin is sufficient to disrupt paracrine transformation by the KSHV vGPCR oncogene". Oncogene 33 (18): 2405–2412. May 2014. doi:10.1038/onc.2013.193. PMID 23708663. 
  18. ↑ 18.0 18.1 "4E-BP1 Is a Tumor Suppressor Protein Reactivated by mTOR Inhibition in Head and Neck Cancer". Cancer Research 79 (7): 1438–1450. April 2019. doi:10.1158/0008-5472.CAN-18-1220. PMID 30894372. 
  19. ↑ 19.0 19.1 19.2 "Metabolic actions of insulin-like growth factor-I in normal physiology and diabetes". Endocrinology and Metabolism Clinics of North America 41 (2): 425–43, vii-viii. June 2012. doi:10.1016/j.ecl.2012.04.017. PMID 22682639. 
  20. ↑ 20.0 20.1 "Role of IGF-I signaling in muscle bone interactions". Bone 80: 79–88. November 2015. doi:10.1016/j.bone.2015.04.036. PMID 26453498. 
  21. ↑ "The relative roles of growth hormone and IGF-1 in controlling insulin sensitivity". The Journal of Clinical Investigation 113 (1): 25–27. January 2004. doi:10.1172/JCI200420660. PMID 14702105. 
  22. ↑ "Mechano-growth factor reduces loss of cardiac function in acute myocardial infarction". Heart, Lung & Circulation 17 (1): 33–39. February 2008. doi:10.1016/j.hlc.2007.04.013. PMID 17581790. 
  23. ↑ 23.0 23.1 "The role of recombinant insulin-like growth factor I in the treatment of the short child". Current Opinion in Pediatrics 19 (4): 458–464. August 2007. doi:10.1097/MOP.0b013e3282094126. PMID 17630612. 
  24. ↑ "Growth Hormone Receptor Deficiency is Associated With a Major Reduction in Pro-aging Signaling, Cancer and Diabetes in Humans". Science Translational Medicine 3 (70): 70ra13. February 2011. doi:10.1126/scitranslmed.3001845. PMID 21325617. 
  25. ↑ World Clinics: Dermatology – Acne. JP Medical Ltd. 2014. ISBN 9789350909768. https://books.google.com/books?id=880iAwAAQBAJ&pg=PA75. 
  26. ↑ "Expert consensus document: A consensus on the medical treatment of acromegaly". Nature Reviews. Endocrinology 10 (4): 243–248. April 2014. doi:10.1038/nrendo.2014.21. PMID 24566817. 
  27. ↑ "Acromegaly: a challenging condition to diagnose". International Journal of General Medicine 11: 337–343. August 2018. doi:10.2147/IJGM.S169611. PMID 30197531. 
  28. ↑ "Association between Insulin-Like Growth Factor- 1 and Severity of Liver Disease in Patients with Liver Cirrhosis". Afro-Egyptian Journal of Infectious and Endemic Diseases 11 (2): 208–215. 2021-06-01. doi:10.21608/aeji.2021.61888.1136. ISSN 2090-7613. https://aeji.journals.ekb.eg/article_174095.html. 
  29. ↑ "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. March 2014. doi:10.1016/j.cmet.2014.02.006. PMID 24606898. 
  30. ↑ "Over-stimulation of insulin/IGF-1 signaling by western diet may promote diseases of civilization: lessons learnt from laron syndrome". Nutrition & Metabolism 8: 41. June 2011. doi:10.1186/1743-7075-8-41. PMID 21699736. 
  31. ↑ "Spuriously Elevated Serum IGF-1 in Adult Individuals with Delayed Puberty: A Diagnostic Pitfall". International Journal of Endocrinology 2010: 1–4. 2010. doi:10.1155/2010/370692. PMID 20862389. 
  32. ↑ 32.0 32.1 32.2 "Monitoring of acromegaly: what should be performed when GH and IGF-1 levels are discrepant?". Clinical Endocrinology 71 (2): 166–170. August 2009. doi:10.1111/j.1365-2265.2009.03556.x. PMID 19226264. 
  33. ↑ "Bronchial carcinoid secreting insulin-like growth factor-1 with acromegalic features". The Annals of Thoracic Surgery 88 (4): 1350–1352. October 2009. doi:10.1016/j.athoracsur.2009.02.042. PMID 19766843. 
  34. ↑ "Does milk intake promote prostate cancer initiation or progression via effects on insulin-like growth factors (IGFs)? A systematic review and meta-analysis". Cancer Causes & Control 28 (6): 497–528. June 2017. doi:10.1007/s10552-017-0883-1. PMID 28361446. 
  35. ↑ 35.0 35.1 "Statement on possible carcinogenic hazard to consumers from insulin-like growth factor-1 (IGF-1) in the diet. assets.publishing.service.gov.uk. Retrieved 4 February 2023.
  36. ↑ "Analysis of the IGF-system in milk from farm animals - Occurrence, regulation, and biomarker potential". Growth Hormone & IGF Research 35: 1–7. August 2017. doi:10.1016/j.ghir.2017.05.004. PMID 28544872. 
  37. ↑ "Association between IGF-1 levels ranges and all-cause mortality: A meta-analysis". Aging Cell 21 (2): e13540. February 2022. doi:10.1111/acel.13540. PMID 35048526. 
  38. ↑ "IGF-1 and cardiovascular disease". Growth Hormone & IGF Research 45: 6–16. April 2019. doi:10.1016/j.ghir.2019.01.002. PMID 30735831. 
  39. ↑ "Association between insulin-like growth factor-1 and cardiovascular events: a systematic review and dose-response meta-analysis of cohort studies". Journal of Endocrinological Investigation 45 (12): 2221–2231. December 2022. doi:10.1007/s40618-022-01819-1. PMID 35596917. 
  40. ↑ "Relationship between serum insulin-like growth factor 1 levels and ischaemic stroke: a systematic review and meta-analysis". BMJ Open 12 (6): e045776. June 2022. doi:10.1136/bmjopen-2020-045776. PMID 35705353. 
  41. ↑ "Potential Utility of rhIGF-1 in Neuromuscular and/Or Degenerative Disease". Ciba Foundation Symposium 196 - Growth Factors as Drugs for Neurological and Sensory Disorders. Novartis Foundation Symposia. 196. 2007. pp. 18–27; discussion 27–38. doi:10.1002/9780470514863.ch3. ISBN 9780470514863. 
  42. ↑ "Genentech Discontinues IGF-I Drug Development Effort in Diabetes" (Press release). Genentech. 5 September 1997. Archived from the original on 7 December 2019. Retrieved 15 March 2013.
  43. ↑ "A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro". The Journal of Laboratory and Clinical Medicine 49 (6): 825–836. June 1957. PMID 13429201. 

External links

de:IGF-1



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