IGFBP-2 is an unglycosylated polypetide of 31.3 kDa and is one of the six circulating proteins that bind insulin-like growth factor (IGF)-I and -II with high affinity. Cleavage of signal peptide from the precursor protein generates the 31 kDa mature IGFBP-2, which consists of N- and C-terminal cysteine rich regions (1,2). Both N- and C-terminal regions of IGFBP-2 bind IGF-I and IGF-II preventing their interaction with IGF-1 receptor (2). IGFBP-2 mainly exists in non-glycosylated and non-phosphorylated form (3,4).

IGFBP-2 is a widely expressed protein with functions in bone and skeletal muscle development, and regulation of body growth and composition (5). Pure congenic IGFBP2 -/- mice show gender and bone compartment-specific phenotypes (6). IGFBP-2 overexpression mice have reduced body weight suggesting a role in postnatal growth by potentially regulating IGF-I bioavailability (7).

IGFBP-2 levels in circulation are influenced under different metabolism and malignant states (5). IGFBP-2 levels are high in cord serum from term infants, in contrast plasma IGFBP-2 levels in adults are lower (8). IGFBP-2 levels in adults are subjected to minimal daily fluctuations suggesting that postprandial changes in glucose and insulin levels do not influence IGFBP-2 levels (8). Compared to normal adults, IGFBP-2 levels are elevated in hypopituitary adults suggesting regulation by growth hormone (8). Extreme physical exercise results in elevated serum IGFBP-2 levels in men and women (5). Circulating IGFBP-2 levels are high in anorexia nervosa patients and suppressed in obesity and Type 2 diabetes (5). Overexpression of IGFBP-2 protects against obesity and diabetes by inhibiting adipogenesis and modulating insulin sensitivity (9,10). In contrast to Type 2 diabetes, IGFBP-2 levels are increased in Type 1 diabetes suggesting regulation by insulin sensitivity (11). Low postpartum IGFBP-2 levels are associated with the development of Type 2 diabetes in women with history of gestational diabetes mellitus (12).

IGFBP-2 levels are also altered in intra-uterine growth retardation (IUGR) and small for gestational age (SGA) cases. In IUGR cord serum levels of IGFBP-2 are elevated and levels are low in pre-pubertal and pubertal SGA subjects (5). IGFBP-2 role in cancer progression is indicated by elevated levels in several malignancies like prostate, ovarian, breast and gastric cancer (5). In colon cancer IGFBP-2 levels are elevated in plasma and is associated with increased risk of mortality (13). Recently, IGFBP-2 was identified as an early stage biomarker in invasive ductal adenocarcinoma of pancreas (14) and elevated serum IGFBP-2 levels were reported in idiopathic pulmonary fibrosis and Lupus nephritis patients (15,16). Circulating levels of IGFBP-2 may be an important biomarker of different metabolic and malignant states.

References:
1. Binkert C, Landwehr J, Mary JL, Schwander J, Heinrich G. Cloning, sequence analysis and expression of a cDNA encoding a novel insulin-like growth factor binding protein (IGFBP-2). EMBO J 1989;8:2497–502.
2. Galea CA, Mobli M, McNeil KA, Mulhern TD, Wallace JC, King GF, et al. Insulinlike growth factor binding protein-2: NMR analysis and structural characterization of the N-terminal domain. Biochimie 2012;94:608–16.
3. Firth SM, Baxter RC. Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev 2002;23:824–54.
4. Coverley JA, Baxter RC. Phosphorylation of insulin-like growth factor binding proteins. Mol Cell Endocrinol 1997;128:1–5
5. Russo VC, Azar WJ, Yau SW, Sabin MA, Werther GA. IGFBP-2: The dark horse in metabolism and cancer. Cytokine Growth Factor Rev. 2015 Jun;26(3):329-46
6. DeMambro VE, Clemmons DR, Horton LG, Bouxsein ML, Wood TL, Beamer WG, et al. Gender-specific changes in bone turnover and skeletal architecture in IGFBP-2-null mice. Endocrinology 2008;149:2051–61.
7. Hoeflich A, Wu M, Mohan S, Foll J, Wanke R, Froehlich T, et al. Overexpression of insulin-like growth factor-binding protein-2 in transgenic mice reduces postnatal body weight gain. Endocrinology 1999;140:5488–96.
8. Clemmons DR, Snyder DK, Busby Jr WH. Variables controlling the secretion of insulin-like growth factor binding protein-2 in normal human subjects. J Clin Endocrinol Metab 1991;73:727–33.
9. Wheatcroft SB, Kearney MT, Shah AM, Ezzat VA, Miell JR, Modo M, et al. IGFbinding protein-2 protects against the development of obesity and insulin resistance. Diabetes 2007;56:285–94.
10. Hedbacker K, Birsoy K, Wysocki RW, Asilmaz E, Ahima RS, Farooqi IS, et al. Antidiabetic effects of IGFBP2, a leptin-regulated gene. Cell Metab 2010;11:11–22.
11. Frystyk J, Skjaerbaek C, Vestbo E, Fisker S, Orskov H. Circulating levels of free insulin-like growth factors in obese subjects: the impact of type 2 diabetes. Diabetes Metab Res Rev 1999;15:314–22.
12. Lappas M, Jinks D, Shub A, Willcox JC, Georgiou HM, Permezel M. Postpartum IGF-I and IGFBP-2 levels are prospectively associated with the development of type 2 diabetes in women with previous gestational diabetes mellitus. Diabetes Metab. 2016.
13. Liou J-M, Shun C-T, Liang J-T, Chiu H-M, Chen M-J, Chen CC, et al. Plasma insulin- like growth factor-binding protein-2 levels as diagnostic and prognostic bio- marker of colorectal cancer. J Clin Endocrinol Metab 2010;95:1717–20.
14. Yoneyama T, Ohtsuki S, Honda K et al. Identification of IGFBP2 and IGFBP3 As Compensatory Biomarkers for CA19-9 in Early-Stage Pancreatic Cancer Using a Combination of Antibody-Based and LC-MS/MS-Based Proteomics. PLoS One. 2016;11(8)
15. Guiot J, Bondue B, Henket M, Corhay JL, Louis R. Raised serum levels of IGFBP-1 and IGFBP-2 in idiopathic pulmonary fibrosis. BMC Pulm Med. 2016;16(1):86.
16. Ding H, Kharboutli M, Saxena R, Wu T. Insulin-like growth factor binding protein-2 as a novel biomarker for disease activity and renal pathology changes in lupus nephritis. Clin Exp Immunol. 2016 Apr;184(1):11
17. HHS Publication, 5th ed., 2007. Biosafety in Microbiological and Biomedical Laboratories. Available http://www.cdc.gov/biosafety/publications/bmbl5/BMBL5
18. DHHS (NIOSH) Publication No. 78–127, August 1976. Current Intelligence Bulletin 13 – Explosive Azide Hazard. Available http:// www.cdc.gov/niosh.
19. DOT
20. Kricka L. Interferences in immunoassays – still a threat. Clin Chem 2000; 46: 1037–1038.

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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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Legro R, Dodson W, Estes S, Kunselman A, Coutifaris C, Dokras A. Effect of Weight Loss and Hormonal Suppression Alone and in Combination on Bioactive Gut and Ovarian Peptide Hormones in Women with Polycystic Ovary Syndrome. Journal of the Endocrine Society, Volume 3, Issue Supplement_1, April-May 2019, MON-233, https://doi.org/10.1210/js.2019-MON-233

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Richard Legro, William Dodson, Stephanie Estes, Allen Kunselman, Christos Coutifaris, Anuja Dokras, MON-233 Effect of Weight Loss and Hormonal Suppression Alone and in Combination on Bioactive Gut and Ovarian Peptide Hormones in Women with Polycystic Ovary Syndrome, Journal of the Endocrine Society, Volume 3, Issue Supplement_1, April-May 2019, MON–233, https://doi.org/10.1210/js.2019-

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Shah A, Dodson WC, Kris-Etherton PM, Kunselman AR, Stetter CM, Gnatuk CL, Estes SJ, Allison KC, Sarwer DB, Sluss PM, Coutifaris C, Dokras A, Legro RS. Effects of Oral Contraception and Lifestyle Modification on Incretins and TGF-ß Superfamily Hormones in PCOS. J Clin Endocrinol Metab. 2021 Jan 1;106(1):108-119. doi: 10.1210/clinem/dgaa682. PMID: 32968804; PMCID: PMC7765645

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