Circulating Insulin-like Growth Factor-1 and Insulin-like Growth Factor Binding Protein-3 predict Three-months Outcome after Ischemic Stroke

Moritz Armbrust; Hans Worthmann; Reinhard Dengler; Helmut Schumacher; Ralf Lichtinghagen; Christoph Cyrill Eschenfelder; Matthias Endres; Martin Ebinger

doi:10.1055/s-0043-103965

Experimental and Clinical Endocrinology & Diabetes, Table of Contents

Exp Clin Endocrinol Diabetes 2017; 125(07): 485-491
DOI: 10.1055/s-0043-103965

Article

Circulating Insulin-like Growth Factor-1 and Insulin-like Growth Factor Binding Protein-3 predict Three-months Outcome after Ischemic Stroke

Moritz Armbrust

¹Center for Stroke Research Berlin, Charité – Universitätsmedizin Berlin, Charitéplatz 1, Berlin, Germany

,

Hans Worthmann

³Department of Neurology, Hannover Medical School, Carl-Neuberg-Strasse 1, Hannover, Germany

,

Reinhard Dengler

³Department of Neurology, Hannover Medical School, Carl-Neuberg-Strasse 1, Hannover, Germany

,

Helmut Schumacher

⁵Statistical Consultant, Ingelheim, Germany

,

Ralf Lichtinghagen

⁶Institute for Clinical Chemistry, Hannover Medical School, Carl-Neuberg-Strasse 1, Hannover, Germany

,

Christoph Cyrill Eschenfelder

⁴Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany

,

Matthias Endres

¹Center for Stroke Research Berlin, Charité – Universitätsmedizin Berlin, Charitéplatz 1, Berlin, Germany

²Department of Neurology, Charité – Universitätsmedizin Berlin, Charitéplatz 1, Berlin, Germany

,

Martin Ebinger

¹Center for Stroke Research Berlin, Charité – Universitätsmedizin Berlin, Charitéplatz 1, Berlin, Germany

²Department of Neurology, Charité – Universitätsmedizin Berlin, Charitéplatz 1, Berlin, Germany

› Author Affiliations

Abstract

Objective

Reports on neuroprotective effects of Insulin-like growth factor-1 (IGF-1) and Insulin-like growth factor binding protein-3 (IGFBP-3) in ischemic brain tissue are inconsistent. The aim of this study was to determine if plasma levels of IGF-1 and IGFBP-3 in acute stroke patients are indicative of 3 months functional outcome.

Methods

Plasma levels were measured via chemiluminescence immunoassay in heparin blood samples of patients included in the EARLY trial (NCT00562588). Plasma samples were drawn on admission and 8 days post-stroke. Neurological deficits were assessed via modified Rankin Scale (mRS) 3 months post-stroke, resulting in favorable (mRS=0–2) or unfavorable (mRS=3–6) outcome. A multiple binary logistic regression including IGF-1 and IGFBP-3 levels and confounders was conducted.

Results

Out of 404 included patients, 89 patients had an unfavorable outcome. Mean mRS on admission as well as 3 months post-stroke was 2 (±1). Low IGF-1 levels (day 8) were independently associated with a decreased risk of an unfavorable outcome (OR 0.61; 95%CI 0.37–0.99; p=0.044). Low IGFBP-3 levels (day 8) were independently associated with an unfavorable outcome (OR 2.75; 95%CI 1.56–4.84; p<0.001).

Interpretation

Low IGFBP-3 levels and high IGF-1 levels in the subacute phase are predictive of unfavorable outcome 3 months after stroke.

Key words

neuroprotection - acute cerebral infarction - modified Rankin Scale

Full Text

References

References
1 Feigin VL, Forouzanfar MH, Krishnamurthi R. et al. Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet (London, England) 2014; 383: 245-254
2 Banks JL, Marotta CA. Outcomes validity and reliability of the modified Rankin scale: Implications for stroke clinical trials: A literature review and synthesis. Stroke; a journal of cerebral circulation 2007; 38: 1091-1096
3 Baron JC. Stroke: Predicting outcome after ischemic stroke-hard but achievable. Nature reviews Neurology 2011; 7: 253-254
4 Whiteley W, Chong WL, Sengupta A. et al. Blood markers for the prognosis of ischemic stroke: a systematic review. Stroke; a journal of cerebral circulation 2009; 40: e380-e389
5 Simats A, Garcia-Berrocoso T, Montaner J. Neuroinflammatory biomarkers: From stroke diagnosis and prognosis to therapy. Biochimica et biophysica acta. 2015;
6 Aberg D. Role of the growth hormone/insulin-like growth factor 1 axis in neurogenesis. Endocrine development 2010; 17: 63-76
7 Joseph D’Ercole A, Ye P. Expanding the mind: Insulin-like growth factor I and brain development. Endocrinology 2008; 149: 5958-5962
8 Collett-Solberg PF, Cohen P. Genetics, chemistry, and function of the IGF/IGFBP system. Endocrine 2000; 12: 121-136
9 Jogie-Brahim S, Feldman D, Oh Y. Unraveling insulin-like growth factor binding protein-3 actions in human disease. Endocr Rev 2009; 30: 417-437
10 Martin JL, Baxter RC. Signalling pathways of insulin-like growth factors (IGFs) and IGF binding protein-3. Growth factors (Chur, Switzerland) 2011; 29: 235-244
11 Kielczewski JL, Hu P, Shaw LC. et al. Novel protective properties of IGFBP-3 result in enhanced pericyte ensheathment, reduced microglial activation, increased microglial apoptosis, and neuronal protection after ischemic retinal injury. The American journal of pathology 2011; 178: 1517-1528
12 Chang KH, Chan-Ling T, McFarland EL. et al. IGF binding protein-3 regulates hematopoietic stem cell and endothelial precursor cell function during vascular development. Proc Natl Acad Sci USA 2007; 104: 10595-10600
13 Lofqvist C, Chen J, Connor KM. et al. IGFBP3 suppresses retinopathy through suppression of oxygen-induced vessel loss and promotion of vascular regrowth. Proc Natl Acad Sci USA 2007; 104: 10589-10594
14 Schuler-Luttmann S, Monnig G, Enbergs A. et al. Insulin-like growth factor-binding protein-3 is associated with the presence and extent of coronary arteriosclerosis. Arteriosclerosis, thrombosis, and vascular biology 2000; 20: E10-E15
15 Johnsen SP, Hundborg HH, Sorensen HT. 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: 5937-5941
16 Aberg D, Jood K, Blomstrand C. et al. Serum IGF-I levels correlate to improvement of functional outcome after ischemic stroke. J Clin Endocrinol Metab 2011; 96: E1055-E1064
17 Bondanelli M, Ambrosio MR, Onofri A. et al. Predictive value of circulating insulin-like growth factor I levels in ischemic stroke outcome. J Clin Endocrinol Metab 2006; 91: 3928-3934
18 Endres M, Piriz J, Gertz K. et al. Serum insulin-like growth factor I and ischemic brain injury. Brain research 2007; 1185: 328-335
19 Denti L, Annoni V, Cattadori E. et al. Insulin-like growth factor 1 as a predictor of ischemic stroke outcome in the elderly. Am J Med 2004; 117: 312-317
20 Ebinger M, Ipsen N, Leonards CO. et al. Circulating Insulin-like Growth Factor Binding Protein-3 Predicts One-year Outcome after Ischemic Stroke. Experimental and clinical endocrinology & diabetes: Official journal, German Society of Endocrinology [and] German Diabetes Association 2015; 123: 461-465
21 Dengler R, Diener HC, Schwartz A. et al. Early treatment with aspirin plus extended-release dipyridamole for transient ischaemic attack or ischaemic stroke within 24h of symptom onset (EARLY trial): A randomised, open-label, blinded-endpoint trial. The Lancet Neurology 2010; 9: 159-166
22 Worthmann H, Dengler R, Schumacher H. et al. Monocyte chemotactic protein-1 as a potential biomarker for early anti-thrombotic therapy after ischemic stroke. International Journal of Molecular Sciences 2012; 13: 8670-8678
23 Elmlinger MW, Kuhnel W, Weber MM. et al. Reference ranges for two automated chemiluminescent assays for serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3). Clin Chem Lab Med 2004; 42: 654-664
24 Brabant G, von zur Muhlen A, Wuster C. et al. Serum insulin-like growth factor I reference values for an automated chemiluminescence immunoassay system: Results from a multicenter study. Hormone research 2003; 60: 53-60
25 Kooijman R, Sarre S, Michotte Y. et al. Insulin-like growth factor I: A potential neuroprotective compound for the treatment of acute ischemic stroke?. Stroke; a journal of cerebral circulation 2009; 40: e83-e88
26 Zechariah A, ElAli A, Doeppner TR. et al. Vascular endothelial growth factor promotes pericyte coverage of brain capillaries, improves cerebral blood flow during subsequent focal cerebral ischemia, and preserves the metabolic penumbra. Stroke; a journal of cerebral circulation 2013; 44: 1690-1697
27 Wang J, Tang Y, Zhang W. et al. Insulin-like growth factor-1 secreted by brain microvascular endothelial cells attenuates neuron injury upon ischemia. The FEBS journal 2013; 280: 3658-3668
28 Guan J, Williams C, Gunning M. et al. The effects of IGF-1 treatment after hypoxic-ischemic brain injury in adult rats. J Cereb Blood Flow Metab 1993; 13: 609-616
29 Bergstedt K, Wieloch T. Changes in insulin-like growth factor 1 receptor density after transient cerebral ischemia in the rat. Lack of protection against ischemic brain damage following injection of insulin-like growth factor 1. J Cereb Blood Flow Metab 1993; 13: 895-898
30 Schwab S, Spranger M, Krempien S. et al. Plasma insulin-like growth factor I and IGF binding protein 3 levels in patients with acute cerebral ischemic injury. Stroke; a journal of cerebral circulation 1997; 28: 1744-1748
31 Preston E, Sutherland G, Finsten A. Three openings of the blood-brain barrier produced by forebrain ischemia in the rat. Neurosci Lett 1993; 149: 75-78
32 Guan J, Skinner SJ, Beilharz EJ. et al. The movement of IGF-I into the brain parenchyma after hypoxic-ischaemic injury. Neuroreport 1996; 7: 632-636
33 Arany E, Afford S, Strain AJ. et al. Differential cellular synthesis of insulin-like growth factor binding protein-1 (IGFBP-1) and IGFBP-3 within human liver. J Clin Endocrinol Metab 1994; 79: 1871-1876
34 Regan FM, Williams RM, McDonald A. et al. Treatment with recombinant human insulin-like growth factor (rhIGF)-I/rhIGF binding protein-3 complex improves metabolic control in subjects with severe insulin resistance. J Clin Endocrinol Metab 2010; 95: 2113-2122
35 Ito Y, Nakachi K, Imai K. et al. Stability of frozen serum levels of insulin-like growth factor-I, insulin-like growth factor-II, insulin-like growth factor binding protein-3, transforming growth factor beta, soluble Fas, and superoxide dismutase activity for the JACC study. J Epidemiol 2005; 15: S67-S73
36 Wilczak N, Elting JW, Chesik D. et al. Intravenous tissue plasminogen activator in patients with stroke increases the bioavailability of insulin-like growth factor-1. Stroke; a journal of cerebral circulation 2006; 37: 2368-2371