Insulin-like growth factor II (IGF-II) is a 7.5 kDa, 67 amino acid peptide, which is thought to mediate some of the actions of growth hormone (GH).1 IGF-II is synthesized as a prohormone, a polypeptide consisting of A, C, B, D and E domains.1,2 After post-translational modification, the mature IGF-II consists of the A, C, B and D domains, and is structurally homologous to IGF-I and proinsulin. Significant quantities of pro-IGF-II containing the E-peptide extension may also be secreted into the circulation.

In vivo, IGF-II is secreted by the liver and other tissues and is postulated to have mitogenic and metabolic actions at or near the sites of synthesis; this has been termed the paracrine role of IGF-II.1 IGF-II also appears in the peripheral circulation, where it circulates primarily in a high molecular weight tertiary complex with IGF-binding protein-3 (IGFBP-3) and acid-labile subunit.3,4 A smaller proportion of IGF-II may circulate in association with other IGF-binding proteins.4 The proportion of unbound IGF-II in the circulation has been estimated at < 5%.5 Plasma levels of IGF-II are dependent upon adequate levels of GH and other factors, including adequate nutrition.1,6 The actions of IGF-II are mediated by binding to specific cell surface receptors. The IGF-II or type II IGF receptor is a monomeric protein which also serves as the receptor for mannose-6-phosphate.7 The function of the type II IGF receptor is not completely defined. IGF-II binds with lower affinity to the IGF-I type I receptors and the insulin receptors. These latter receptors may mediate the mitogenic and metabolic actions of IGF-II.8,9 Although its specific physiologic role has not been defined, it has been postulated that the interplay of IGF-I and IGF-II with the different cell surface receptors and circulating binding proteins modulates tissue growth.9

In humans and rodents, IGF-II messenger RNA expression is highest during fetal life.9 Type II IGF receptor levels also appear to be high during fetal life, both in fetal tissues and in the circulation.9,10,11 However, fetal plasma levels of IGF-II are relatively low in humans and increase with postnatal age, whereas fetal levels are higher than postnatal levels in other species.9 Postnatal plasma IGF-II levels are assumed to be at maximal levels, since administration of GH does not result in increased IGF-II levels (unlike IGF- I levels, which increase).12 Postnatal plasma IGF-II levels show a moderate age- related increase throughout childhood and puberty, and there is no significant variability during the day.6,13

The assay of plasma IGF-II is complicated by the presence of IGF-binding proteins, which may sequester IGF-II in the reaction mixture.6,12 Various methods have been devised to separate the IGF-II and IGF-binding proteins prior to assay. Size-exclusion gel chromatography in acid is considered to be optimal, 14 but this procedure is not feasible for routine use. Acidification followed by ethanol or acetone precipitation of the IGF fraction gives results which are similar to acid-chromatography.15

References:
1. Daughaday WH, Rotwein P: Insulin like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum and tissue concentrations. Endocrin Rev 10:68-91, 1989.
2. Bell GI, Merryweather JP, Sanchez-Pescador R, Stempien MM, Priestley L, Scott J, Rall LB: Sequence of a cDNA clone encoding human preproinsulin- like growth factor II. Nature 310:775-777, 1984.
3. Baxter RC, Martin JL, Beniac VA: High molecular weight insulin-like growth factor binding protein complex. J Biol Chem 264:11843-11848, 1989.
4. Rechler M: Insulin-like growth factor binding proteins. Vit Horm 47:1-114, 1993.
5. Zapf J, Hauri C, Waldvogel M, Froesch ER: Acute metabolic effects and half-lives of intravenously administered insulin-like growth factors I and II in normal and hypophysectomized rats. J Clin Invest 77:1768-1775, 1986.
6. Lee PDK, Rosenfeld RG: Clinical utility of insulin-like growth factor assays. Pediatrician 14:154-161, 1987.
7. Morgan DO, Edman JC, Standring DN, Fried VA, Smith MC, Roth RA, Rutter WJ: Insulin-like growth factor II receptor as a multifunctional binding protein. Nature 329:301-307, 1987.
8. Conover CA, Misra P, Hintz RL, Rosenfeld RG: Effect of an anti-insulin-like growth factor I receptor antibody on insulin-like growth factor II stimulation of DNA synthesis in human fibroblasts. Biochem Biophys Res Commun 139:501-508, 1986.
9. Gluckman PD, Ambler GR: What is the function of circulating insulin-like growth factor-2 in postnatal life. Mol Cell Endocrinol 92:C1-C3, 1993.
10. Lee PDK, Hintz RL, Rosenfeld RG, Benitz WE: Presence of insulin growth factor receptors and lack of insulin receptors on fetal bovine aortic smooth muscle cells. In Vitro Cell Dev Biol 24:921-926, 1988.
11. Kiess W, Greenstein LA, White RM, Lee L, Rechler MM, Nissley SP: Type II insulin-like growth factor receptor is present in rat serum. Proc Nat Acad Sci USA 84:7720-7724, 1987.
12. Hintz RL: The somatomedins. Adv Pediatr 28:293-317, 1981.
13. Rosenfeld RG, Wilson DM, Lee PDK, Hintz RL: lnsulin-like growth factors I and II in evaluation of growth retardation. J Pediatr 109:428-433, 1986.
14. Soliman AT, Hassan AEH1, Aref MK, Hintz RL, Rosenfeld RG, Rogol AD: Serum insulin-like growth factors I and IT concentrations and growth hormone and insulin responses to arginine infusion in children with protein-calorie malnutrition before and after nutritional rehabilitation. Pediatr Res 20:1122-1130, 1986.
15. Powell DR, Rosenfeld RG, Baker BK, Liu F, Hintz RL: Serum somatomedin levels in adults with chronic renal failure: the importance of measuring insulin-like growth factor I (IGF-I) and IGF-II in acid-chromatographed uremic serum. J Clin Endocrinol Metab 63:1186-1192, 1986.
16. HHS Publication, 5th ed., 2007. Biosafety in Microbiological and Biomedical Laboratories. Available http://www.cdc.gov/biosafety/publications/bmbl5/BMBL5
17. DHHS (NIOSH) Publication No. 78–127, August 1976. Current Intelligence Bulletin 13 – Explosive Azide Hazard. Available http:// www.cdc.gov/niosh.
18. Kricka L. Interferences in immunoassays – still a threat. Clin Chem 2000; 46: 1037–1038.

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Babiker A, Al Noaim K, Al Swaid A, et al. Short stature with low insulin-like growth factor 1 availability due to pregnancy-associated plasma protein A2 deficiency in a Saudi family. Clin Genet. 2021;100(5):601-606. doi: 10.1111/cge.14030.

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Bøtkjær JA, Pors SE, Petersen TS, Kristensen SG, Jeppesen JV, Oxvig C, Andersen CY. Transcription profile of the insulin-like growth factor signaling pathway during human ovarian follicular development. Assist Reprod Genet
. 2019 May;36(5):889-903. doi: 10.1007/s10815-019-01432-x. Epub 2019 Mar 15.

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DiPrisco B, Kumar A, Kalra B, Savjani GV, Michael Z, Farr O, Papathanasiou AE, Christou H, Mantzoros C. Placental proteases PAPP-A and PAPP-A2, the binding proteins they cleave (IGFBP-4 and -5), and IGF-I and IGF-II: Levels in umbilical cord blood and associations with birth weight and length. Metabolism. 2019 Nov;100:153959. doi: 10.1016/j.metabol.2019.153959. Epub 2019 Aug 8.

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Donegan D, Bale LK, Conover CA. PAPP-A in normal human mesangial cells: effect of inflammation and factors related to diabetic nephropathy. J Endocrinol. 2016 Oct;231(1):71-80. doi: 10.1530/JOE-16-0205. Epub 2016 Aug 12. PMID: 27519211.

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Hjortebjerg R, Høgdall C, Hansen KH, Høgdall E, Frystyk J. The IGF–PAPP-A–Stanniocalcin axis in serum and ascites associates with prognosis in patients with ovarian cancer. Int J Mol Sci. 2024;25(2014):1-16. doi:10.3390/ijms25042014.

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Hjortebjerg R, Pedersen DA, Mengel-From J, Jørgensen LH, Christensen K, Frystyk J. Heritability and circulating concentrations of pregnancy-associated plasma protein-A and stanniocalcin-2 in elderly monozygotic and dizygotic twins. Front Endocrinol (Lausanne). 2023;14:1193742. doi:10.3389/fendo.2023.1193742.

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Kazemi M, Jarrett BY, Parry SA, Thalacker-Mercer AE, Hoeger KM, Spandorfer SD, Lujan ME. . Osteosarcopenia in Reproductive-Aged Women with Polycystic Ovary Syndrome: A Multicenter Case-Control Study. J Clin Endocrinol Metab. 2020 Sep 1;105(9):e3400-e3414. doi: 10.1210/clinem/dgaa426

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Kumar A, Kalra B, Kommareddy V, Chowdavarapu K, Mistry S, Savjani G, Oxvig C. Development of Well Characterized ELISAs for Bound and Unbound Insulin-Like Growth Factors and their Binding Proteins. Poster presented at 98th Annual Endocrine Society Meeting; 2016 Apr 1-3; Boston, MA.

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Martín-Rivada Á, Guerra Cantera S, Campillo-Calatayud A, Andrés-Esteban EM, Sánchez Holgado M, Martos-Moreno GÁ, Pozo J, Güemes M, Soriano-Guillén L, Pellicer A, Oxvig C, Frystyk J, Chowen JA, Barrios V, Argente J.Pappalysins and Stanniocalcin and Their Relationship With the Peripheral IGF Axis in Newborns and During DevelopmentJ Clin Endocrinol Metab. 2022 Sep 28;107(10):2912-2924. doi: 10.1210/clinem/dgac453. PMID: 35902207.

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Vicente Barrios, Álvaro Martín-Rivada, Gabriel Á Martos-Moreno, Sandra Canelles, Francisca Moreno-Macián, Carmen De Mingo-Alemany, Maurizio Delvecchio, Roberta Pajno, Danilo Fintini, Julie A Chowen, Jesús Argente, Increased IGFBP Proteolysis, IGF-I Bioavailability, and Pappalysin Levels in Children With Prader-Willi Syndrome, The Journal of Clinical Endocrinology & Metabolism, Volume 109, Issue 9, September 2024, Pages e1776–e1786, https://doi.org/10.1210/clinem/dgad754

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