Serum IGF-1 level as a prognostic marker for acute ischemic stroke: a systematic review
-
Shayan Roshdi Dizaji
,
Hamed Zarei
,
Sajjad Jabermoradi
,
Parsa Paridari
,
Mostafa Hosseini
,
Mahmoud Yousefifard
Abstract
Objective: Assessing the risk levels of patients with acute ischemic stroke (AIS) can assist in making informed choices about their treatment and rehabilitation. To assess the prognostic value of serum insulin-like growth factor-1 (IGF-1) in neurological deficit (National Institutes of Health Stroke Scale [NIHSS]), functional independence (Modified Rankin Scale [mRS]), and mortality following AIS. Methods: The search encompassed Medline, Embase, Scopus, and Web of Science until June 2023. Two autonomous researchers incorporated articles by the established inclusion and exclusion criteria. The quality of the included studies were assessed using the quality assessment of prognostic accuracy studies (QUAPAS) tool. Results: Ten articles were included, with evidence suggesting that IGF-1 may have prognostic value in AIS outcomes. Several studies reported positive associations between IGF-1 levels, reduced neurological deficits, improved functional independence, and lower mortality. Additionally, intraindividual fluctuations in IGF-1 after AIS were identified as a potential predictor of recovery in functional independence, though significant inconsistencies exist in the findings. Conclusion: The available studies with a very low level of evidence are not sufficient to firmly endorse the applicability of IGF-1 as a prognostic factor for mortality, neurological disability, and functional independence.
1. Wang X. Correlation between serum neuron specific enolase level and neuron injury index and neuron apoptosis index in patients with brain injury. ACTA MEDICA MEDITERRANEA. 2021;37(2):791-4.
2. Tsao CW, Aday AW, Almarzooq ZI, Anderson CAM, Arora P, Avery CL, et al. Heart disease and stroke statistics-2023 update: a report from the American Heart Association. Circulation. 2023;147(8):e93-e621.
3. Whiteley W, Wardlaw J, Dennis M, Lowe G, Rumley A, Sattar N, et al. The use of blood biomarkers to predict poor outcome after an acute transient ischemic attack or ischemic stroke. Stroke. 2012;43(1):86-91.
4. Xu Q, Tian Y, Peng H, Li H. Copeptin as a biomarker for prediction of prognosis of acute ischemic stroke and transient ischemic attack: a meta-analysis. Hypertens Res. 2017;40(5):465-71.
5. El Husseini N, Laskowitz DT. The role of neuroendocrine pathways in prognosis after stroke. Expert Rev Neurother. 2014;14(2):217-32.
6. Bondanelli M, Ambrosio MR, Zatelli MC, Basaglia N, Degli Uberti EC. Prevalence of hypopituitarism in patients with cerebrovascular diseases. J Endocrinol Invest. 2008;31(9 Suppl):16-20.
7. Yakar S, Liu JL, Stannard B, Butler A, Accili D, Sauer B, et al. Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc Natl Acad Sci U S A. 1999;96(13):7324-9.
8. Wrigley S, Arafa D, Tropea D. Insulin-like growth factor 1: at the crossroads of brain development and aging. Front Cell Neurosci. 2017;11:14.
9. Trejo JL, Piriz J, Llorens-Martin MV, Fernandez AM, Bolós M, LeRoith D, et al. Central actions of liver-derived insulin-like growth factor I underlying its pro-cognitive effects. Mol Psychiatry. 2007;12(12):1118-28.
10. Johnsen SP, Hundborg H, Sørensen H, Ørskov H, Tjønneland A, Overvad K, et al. Insulin-like growth factor (IGF) I,-II, and IGF binding protein-3 and risk of ischemic stroke. J Clin Endocrinol Metab. 2005;90(11):5937-41.
11. Saber H, Himali JJ, Beiser AS, Shoamanesh A, Pikula A, Roubenoff R, et al. Serum insulin-like growth factor 1 and the risk of ischemic stroke: the Framingham study. Stroke. 2017;48(7):1760-5.
12. Aberg ND, Brywe KG, Isgaard J. Aspects of growth hormone and insulin-like growth factor-I related to neuroprotection, regeneration, and functional plasticity in the adult brain. ScientificWorldJournal. 2006;6:53-80.
13. Li Y, Yang W, Li J, Zhang Y, Zhang L, Chen S, et al. Relationship between serum insulin-like growth factor 1 levels and ischaemic stroke: a systematic review and meta-analysis. BMJ Open. 2022;12(6):e045776.
14. Guan X, Peng Q, Wang J. Sevoflurane activates MEF2D-mediated Wnt/β-catenin signaling pathway via microRNA-374b-5p to affect renal ischemia/reperfusion injury. Immunopharmacology and immunotoxicology. 2022;44(4):603-12.
15. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.
16. Lee J, Mulder F, Leeflang M, Wolff R, Whiting P, Bossuyt PM. QUAPAS: an adaptation of the QUADAS-2 tool to assess prognostic accuracy studies. Ann Internl Med. 2022;175(7):1010-8.
17. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924-6.
18. Åberg D, Jood K, Blomstrand C, Jern C, Nilsson M, Isgaard J, et al. Serum IGF-I levels correlate to improvement of functional outcome after ischemic stroke. J Clin Endocrinol Metab. 2011;96(7):E1055-E64.
19. Åberg ND, Åberg D, Jood K, Nilsson M, Blomstrand C, Kuhn HG, et al. Altered levels of circulating insulin-like growth factor I (IGF-I) following ischemic stroke are associated with outcome-a prospective observational study. BMC neurology. 2018;18:1-12.
20. Åberg ND, Åberg D, Lagging C, Holmegaard L, Redfors P, Jood K, et al. Association between levels of serum insulin-like growth factor I and functional recovery, mortality, and recurrent stroke at a 7-year follow-up. Experimental and clinical endocrinology & diabetes. 2020;128(05):303-10.
21. Armbrust M, Worthmann H, Dengler R, Schumacher H, Lichtinghagen R, Eschenfelder CC, et al. Circulating insulin-like growth factor-1 and insulin-like growth factor binding protein-3 predict three-months outcome after ischemic stroke. Exp Clin Endocrinol Diabetes. 2017;125(07):485-91.
22. De Smedt A, Brouns R, Uyttenboogaart M, De Raedt S, Moens M, Wilczak N, et al. Insulin-like growth factor I serum levels influence ischemic stroke outcome. Stroke. 2011;42(8):2180-5.
23. Denti L, Annoni V, Cattadori E, Salvagnini MA, Visioli S, Merli MF, et al. Insulin-like growth factor 1 as a predictor of ischemic stroke outcome in the elderly. Am J Med. 2004;117(5):312-7.
24. Fan D, Krishnamurthi R, Harris P, Barber PA, Guan J. Plasma cyclic glycine proline/IGF‐1 ratio predicts clinical outcome and recovery in stroke patients. Ann Clin Transl Neurol. 2019;6(4):669-77.
25. Lee J, Lee J, Lee M, Lim J-S, Kim JH, Yu K-H, et al. Association between serum insulin-like growth factor-1 and neurological severity in acute ischemic stroke. J Clin Neurol (Seoul, Korea). 2021;17(2):206.
26. Mehrpour M, Rahatlou H, Hamzehpur N, Kia S, Safdarian M. Association of insulin-like growth factor-I with the severity and outcomes of acute ischemic stroke. Iranian Journal of Neurology. 2016;15(4):214.
27. yan T, WANG X. Studies of serum insulin-like growth factor-1 level in the patients with acute ischemic stroke and relative influence factors. CAJ. 2018;39(6):412-6.
28. Yasar H, Tombul T, Milanlioglu A. The association between insulin-like growth factor-1 and insulin-like growth factor binding protein-3 levels and clinical prognosis in patients with ischemic stroke. Turkish Journal of Cerebrovascular Diseases. 2015;21:30-5.
29. Landin-Wilhelmsen K, Wilhelmsen L, Lappas G, Rosén T, Lindstedt G, Lundberg PA, et al. 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. Clin Endocrinol (Oxf). 1994;41(3):351-7.
30. Lioutas VA, Alfaro-Martinez F, Bedoya F, Chung CC, Pimentel DA, Novak V. Intranasal insulin and insulin-like growth factor 1 as neuroprotectants in acute ischemic stroke. Transl Stroke Res. 2015;6(4):264-75.
31. Wang J, Tang Y, Zhang W, Zhao H, Wang R, Yan Y, et al. Insulin-like growth factor-1 secreted by brain microvascular endothelial cells attenuates neuron injury upon ischemia. FEBS J. 2013;280(15):3658-68.
32. Kooijman R, Sarre S, Michotte Y, De Keyser J. Insulin-like growth factor I: a potential neuroprotective compound for the treatment of acute ischemic stroke? Stroke. 2009;40(4):e83-8.
33. Bondanelli M, Ambrosio MR, Carli A, Bergonzoni A, Bertocchi A, Zatelli MC, et al. Predictors of pituitary dysfunction in patients surviving ischemic stroke. J Clin Endocrinol Metab. 2010;95(10):4660-8.
34. Beilharz EJ, Russo VC, Butler G, Baker NL, Connor B, Sirimanne ES, et al. Co-ordinated and cellular specific induction of the components of the IGF/IGFBP axis in the rat brain following hypoxic-ischemic injury. Brain Res Mol Brain Res. 1998;59(2):119-34.
35. Bondanelli M, Ambrosio MR, Onofri A, Bergonzoni A, Lavezzi S, Zatelli MC, et al. Predictive value of circulating insulin-like growth factor I levels in ischemic stroke outcome. J Clin Endocrinol Metab. 2006;91(10):3928-34.
36. Gao MM, Wang J, Saposnik G. The art and science of stroke outcome prognostication. Stroke. 2020;51(5):1358-60.
37. Zhang W, Wang W, Kuang L. The relation between insulin-like growth factor 1 levels and risk of depression in ischemic stroke. Int J Geriatr Psychiatry. 2018;33(2):e228-e33.
38. Frystyk J, Hussain M, Skjaerbaek C, Pørksen N, Froesch ER, Orskov H. The pharmacokinetics of free insulin-like growth factor-I in healthy subjects. Growth Horm IGF Res. 1999;9(2):150-6.
39. Sun X, Yao H, Douglas RM, Gu XQ, Wang J, Haddad GG. Insulin/PI3K signaling protects dentate neurons from oxygen-glucose deprivation in organotypic slice cultures. J Neurochem. 2010;112(2):377-88.
40. Hayes CA, Valcarcel-Ares MN, Ashpole NM. Preclinical and clinical evidence of IGF-1 as a prognostic marker and acute intervention with ischemic stroke. J Cereb Blood Flow Metab. 2021;41(10):2475-91.
41. Vincent AM, Mobley BC, Hiller A, Feldman EL. IGF-I prevents glutamate-induced motor neuron programmed cell death. Neurobiol Dis. 2004;16(2):407-16.
42. Heck S, Lezoualc'h F, Engert S, Behl C. Insulin-like growth factor-1-mediated neuroprotection against oxidative stress is associated with activation of nuclear factor kappaB. J Biol Chem. 1999;274(14):9828-35.
43. Chesik D, De Keyser J, Wilczak N. Insulin-like growth factor system regulates oligodendroglial cell behavior: therapeutic potential in CNS. J Mol Neurosci. 2008;35(1):81-90.
44. Chang HC, Yang YR, Wang PS, Kuo CH, Wang RY. Insulin-like growth factor I signaling for brain recovery and exercise ability in brain ischemic rats. Med Sci Sports Exerc. 2011;43(12):2274-80.
45. Guan J, Williams C, Gunning M, Mallard C, Gluckman P. The effects of IGF-1 treatment after hypoxic-ischemic brain injury in adult rats. J Cereb Blood Flow Metab. 1993;13(4):609-16.
46. Clemmons DR, Snyder P, Martin K. Physiology of insulin-like growth factor I. In: Conner RF, ed. UpToDate. Wolters Kluwer. Updated Jan, 2024.
47. Wilczak N, Elting JW, Chesik D, Kema IP, De Keyser J. Intravenous tissue plasminogen activator in patients with stroke increases the bioavailability of insulin-like growth factor-1. Stroke. 2006;37(9):2368-71.
2. Tsao CW, Aday AW, Almarzooq ZI, Anderson CAM, Arora P, Avery CL, et al. Heart disease and stroke statistics-2023 update: a report from the American Heart Association. Circulation. 2023;147(8):e93-e621.
3. Whiteley W, Wardlaw J, Dennis M, Lowe G, Rumley A, Sattar N, et al. The use of blood biomarkers to predict poor outcome after an acute transient ischemic attack or ischemic stroke. Stroke. 2012;43(1):86-91.
4. Xu Q, Tian Y, Peng H, Li H. Copeptin as a biomarker for prediction of prognosis of acute ischemic stroke and transient ischemic attack: a meta-analysis. Hypertens Res. 2017;40(5):465-71.
5. El Husseini N, Laskowitz DT. The role of neuroendocrine pathways in prognosis after stroke. Expert Rev Neurother. 2014;14(2):217-32.
6. Bondanelli M, Ambrosio MR, Zatelli MC, Basaglia N, Degli Uberti EC. Prevalence of hypopituitarism in patients with cerebrovascular diseases. J Endocrinol Invest. 2008;31(9 Suppl):16-20.
7. Yakar S, Liu JL, Stannard B, Butler A, Accili D, Sauer B, et al. Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc Natl Acad Sci U S A. 1999;96(13):7324-9.
8. Wrigley S, Arafa D, Tropea D. Insulin-like growth factor 1: at the crossroads of brain development and aging. Front Cell Neurosci. 2017;11:14.
9. Trejo JL, Piriz J, Llorens-Martin MV, Fernandez AM, Bolós M, LeRoith D, et al. Central actions of liver-derived insulin-like growth factor I underlying its pro-cognitive effects. Mol Psychiatry. 2007;12(12):1118-28.
10. Johnsen SP, Hundborg H, Sørensen H, Ørskov H, Tjønneland A, Overvad K, et al. Insulin-like growth factor (IGF) I,-II, and IGF binding protein-3 and risk of ischemic stroke. J Clin Endocrinol Metab. 2005;90(11):5937-41.
11. Saber H, Himali JJ, Beiser AS, Shoamanesh A, Pikula A, Roubenoff R, et al. Serum insulin-like growth factor 1 and the risk of ischemic stroke: the Framingham study. Stroke. 2017;48(7):1760-5.
12. Aberg ND, Brywe KG, Isgaard J. Aspects of growth hormone and insulin-like growth factor-I related to neuroprotection, regeneration, and functional plasticity in the adult brain. ScientificWorldJournal. 2006;6:53-80.
13. Li Y, Yang W, Li J, Zhang Y, Zhang L, Chen S, et al. Relationship between serum insulin-like growth factor 1 levels and ischaemic stroke: a systematic review and meta-analysis. BMJ Open. 2022;12(6):e045776.
14. Guan X, Peng Q, Wang J. Sevoflurane activates MEF2D-mediated Wnt/β-catenin signaling pathway via microRNA-374b-5p to affect renal ischemia/reperfusion injury. Immunopharmacology and immunotoxicology. 2022;44(4):603-12.
15. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.
16. Lee J, Mulder F, Leeflang M, Wolff R, Whiting P, Bossuyt PM. QUAPAS: an adaptation of the QUADAS-2 tool to assess prognostic accuracy studies. Ann Internl Med. 2022;175(7):1010-8.
17. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924-6.
18. Åberg D, Jood K, Blomstrand C, Jern C, Nilsson M, Isgaard J, et al. Serum IGF-I levels correlate to improvement of functional outcome after ischemic stroke. J Clin Endocrinol Metab. 2011;96(7):E1055-E64.
19. Åberg ND, Åberg D, Jood K, Nilsson M, Blomstrand C, Kuhn HG, et al. Altered levels of circulating insulin-like growth factor I (IGF-I) following ischemic stroke are associated with outcome-a prospective observational study. BMC neurology. 2018;18:1-12.
20. Åberg ND, Åberg D, Lagging C, Holmegaard L, Redfors P, Jood K, et al. Association between levels of serum insulin-like growth factor I and functional recovery, mortality, and recurrent stroke at a 7-year follow-up. Experimental and clinical endocrinology & diabetes. 2020;128(05):303-10.
21. Armbrust M, Worthmann H, Dengler R, Schumacher H, Lichtinghagen R, Eschenfelder CC, et al. Circulating insulin-like growth factor-1 and insulin-like growth factor binding protein-3 predict three-months outcome after ischemic stroke. Exp Clin Endocrinol Diabetes. 2017;125(07):485-91.
22. De Smedt A, Brouns R, Uyttenboogaart M, De Raedt S, Moens M, Wilczak N, et al. Insulin-like growth factor I serum levels influence ischemic stroke outcome. Stroke. 2011;42(8):2180-5.
23. Denti L, Annoni V, Cattadori E, Salvagnini MA, Visioli S, Merli MF, et al. Insulin-like growth factor 1 as a predictor of ischemic stroke outcome in the elderly. Am J Med. 2004;117(5):312-7.
24. Fan D, Krishnamurthi R, Harris P, Barber PA, Guan J. Plasma cyclic glycine proline/IGF‐1 ratio predicts clinical outcome and recovery in stroke patients. Ann Clin Transl Neurol. 2019;6(4):669-77.
25. Lee J, Lee J, Lee M, Lim J-S, Kim JH, Yu K-H, et al. Association between serum insulin-like growth factor-1 and neurological severity in acute ischemic stroke. J Clin Neurol (Seoul, Korea). 2021;17(2):206.
26. Mehrpour M, Rahatlou H, Hamzehpur N, Kia S, Safdarian M. Association of insulin-like growth factor-I with the severity and outcomes of acute ischemic stroke. Iranian Journal of Neurology. 2016;15(4):214.
27. yan T, WANG X. Studies of serum insulin-like growth factor-1 level in the patients with acute ischemic stroke and relative influence factors. CAJ. 2018;39(6):412-6.
28. Yasar H, Tombul T, Milanlioglu A. The association between insulin-like growth factor-1 and insulin-like growth factor binding protein-3 levels and clinical prognosis in patients with ischemic stroke. Turkish Journal of Cerebrovascular Diseases. 2015;21:30-5.
29. Landin-Wilhelmsen K, Wilhelmsen L, Lappas G, Rosén T, Lindstedt G, Lundberg PA, et al. 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. Clin Endocrinol (Oxf). 1994;41(3):351-7.
30. Lioutas VA, Alfaro-Martinez F, Bedoya F, Chung CC, Pimentel DA, Novak V. Intranasal insulin and insulin-like growth factor 1 as neuroprotectants in acute ischemic stroke. Transl Stroke Res. 2015;6(4):264-75.
31. Wang J, Tang Y, Zhang W, Zhao H, Wang R, Yan Y, et al. Insulin-like growth factor-1 secreted by brain microvascular endothelial cells attenuates neuron injury upon ischemia. FEBS J. 2013;280(15):3658-68.
32. Kooijman R, Sarre S, Michotte Y, De Keyser J. Insulin-like growth factor I: a potential neuroprotective compound for the treatment of acute ischemic stroke? Stroke. 2009;40(4):e83-8.
33. Bondanelli M, Ambrosio MR, Carli A, Bergonzoni A, Bertocchi A, Zatelli MC, et al. Predictors of pituitary dysfunction in patients surviving ischemic stroke. J Clin Endocrinol Metab. 2010;95(10):4660-8.
34. Beilharz EJ, Russo VC, Butler G, Baker NL, Connor B, Sirimanne ES, et al. Co-ordinated and cellular specific induction of the components of the IGF/IGFBP axis in the rat brain following hypoxic-ischemic injury. Brain Res Mol Brain Res. 1998;59(2):119-34.
35. Bondanelli M, Ambrosio MR, Onofri A, Bergonzoni A, Lavezzi S, Zatelli MC, et al. Predictive value of circulating insulin-like growth factor I levels in ischemic stroke outcome. J Clin Endocrinol Metab. 2006;91(10):3928-34.
36. Gao MM, Wang J, Saposnik G. The art and science of stroke outcome prognostication. Stroke. 2020;51(5):1358-60.
37. Zhang W, Wang W, Kuang L. The relation between insulin-like growth factor 1 levels and risk of depression in ischemic stroke. Int J Geriatr Psychiatry. 2018;33(2):e228-e33.
38. Frystyk J, Hussain M, Skjaerbaek C, Pørksen N, Froesch ER, Orskov H. The pharmacokinetics of free insulin-like growth factor-I in healthy subjects. Growth Horm IGF Res. 1999;9(2):150-6.
39. Sun X, Yao H, Douglas RM, Gu XQ, Wang J, Haddad GG. Insulin/PI3K signaling protects dentate neurons from oxygen-glucose deprivation in organotypic slice cultures. J Neurochem. 2010;112(2):377-88.
40. Hayes CA, Valcarcel-Ares MN, Ashpole NM. Preclinical and clinical evidence of IGF-1 as a prognostic marker and acute intervention with ischemic stroke. J Cereb Blood Flow Metab. 2021;41(10):2475-91.
41. Vincent AM, Mobley BC, Hiller A, Feldman EL. IGF-I prevents glutamate-induced motor neuron programmed cell death. Neurobiol Dis. 2004;16(2):407-16.
42. Heck S, Lezoualc'h F, Engert S, Behl C. Insulin-like growth factor-1-mediated neuroprotection against oxidative stress is associated with activation of nuclear factor kappaB. J Biol Chem. 1999;274(14):9828-35.
43. Chesik D, De Keyser J, Wilczak N. Insulin-like growth factor system regulates oligodendroglial cell behavior: therapeutic potential in CNS. J Mol Neurosci. 2008;35(1):81-90.
44. Chang HC, Yang YR, Wang PS, Kuo CH, Wang RY. Insulin-like growth factor I signaling for brain recovery and exercise ability in brain ischemic rats. Med Sci Sports Exerc. 2011;43(12):2274-80.
45. Guan J, Williams C, Gunning M, Mallard C, Gluckman P. The effects of IGF-1 treatment after hypoxic-ischemic brain injury in adult rats. J Cereb Blood Flow Metab. 1993;13(4):609-16.
46. Clemmons DR, Snyder P, Martin K. Physiology of insulin-like growth factor I. In: Conner RF, ed. UpToDate. Wolters Kluwer. Updated Jan, 2024.
47. Wilczak N, Elting JW, Chesik D, Kema IP, De Keyser J. Intravenous tissue plasminogen activator in patients with stroke increases the bioavailability of insulin-like growth factor-1. Stroke. 2006;37(9):2368-71.
| Files | ||
| Issue | Vol 9 No 1 (2025): Winter (February) | |
| Section | Systematic review / Meta-analysis | |
| Keywords | ||
| Ischemic Stroke Insulin-Like Growth Factor I Prognosis | ||
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How to Cite
1.
Roshdi Dizaji S, Zarei H, Jabermoradi S, Paridari P, Hosseini M, Yousefifard M. Serum IGF-1 level as a prognostic marker for acute ischemic stroke: a systematic review. Front Emerg Med. 2025;9(1):e7.
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