Download PDF
Exp Clin Endocrinol Diabetes 2015; 123(08): 461-465
DOI: 10.1055/s-0035-1554632
Article
© Georg Thieme Verlag KG Stuttgart · New York

Circulating Insulin-like Growth Factor Binding Protein-3 Predicts One-year Outcome after Ischemic Stroke

M. Ebinger
1   Department of Neurology, Charité – Universitätsmedizin Berlin, Germany
2   Center for Stroke Research Berlin, Charité – Universitätsmedizin Berlin, Germany
,
N. Ipsen
1   Department of Neurology, Charité – Universitätsmedizin Berlin, Germany
2   Center for Stroke Research Berlin, Charité – Universitätsmedizin Berlin, Germany
,
C. O. Leonards
2   Center for Stroke Research Berlin, Charité – Universitätsmedizin Berlin, Germany
,
L. Empl
3   International Graduate Program Medical Neurosciences, Charité – Universitätsmedizin Berlin, Germany
,
L. Hanne
2   Center for Stroke Research Berlin, Charité – Universitätsmedizin Berlin, Germany
,
T. Liman
2   Center for Stroke Research Berlin, Charité – Universitätsmedizin Berlin, Germany
,
K. Mai
4   Department of Endocrinology and Metabolism, Charité – Universitätsmedizin Berlin, Germany
5   Experimental and Clinical Research Centre, Max Delbrück Centre and Charité – Universitätsmedizin Berlin, Germany
,
C. J. Strasburger
4   Department of Endocrinology and Metabolism, Charité – Universitätsmedizin Berlin, Germany
,
J. Spranger
4   Department of Endocrinology and Metabolism, Charité – Universitätsmedizin Berlin, Germany
5   Experimental and Clinical Research Centre, Max Delbrück Centre and Charité – Universitätsmedizin Berlin, Germany
6   German Center for Cardiovascular Research, Charité – Universitätsmedizin Berlin, Germany
,
M. Endres
1   Department of Neurology, Charité – Universitätsmedizin Berlin, Germany
2   Center for Stroke Research Berlin, Charité – Universitätsmedizin Berlin, Germany
6   German Center for Cardiovascular Research, Charité – Universitätsmedizin Berlin, Germany
7   Excellence Cluster NeuroCure, Charité – Universtiätsmedizin Berlin, Germany
8   German Center for Neurodegenerative Diseases, Helmholtz Association of German Research Centres, Germany
› Author Affiliations
Further Information

Publication History

received 06 January 2015
first decision 15 April 2015

accepted 13 May 2015

Publication Date:
11 June 2015 (online)

Also available at
    Permissions and Reprints

Abstract

Background: Insulin-like Growth Factor-1 (IGF-1) and Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) have been ascribed neuroprotective effects. We sought to determine whether levels of IGF-1 and IGFBP-3 predict functional outcome after ischemic stroke.

Methods: IGF-1 and IGFBP-3 levels were measured in the first week after stroke in patients with first ischemic stroke who were enrolled in the Berlin Cream&Sugar Study. National Institutes of Health Stroke Scale (NIHSS) was collected at admission. Lesion volume was determined from acute MRI if available. Functional outcome according to the modified Rankin Scale (mRS) was assessed after one year. In multivariate analyses we identified parameters associated with unfavourable functional outcome (mRS>2).

Results: We included 100 patients. 21 patients had an unfavourable functional outcome. IGF-1 levels were<− 2 standard deviation score (SDS) in 7 patients, and>2 SDS in 12 patients. IGFBP-3 levels were<the 5th percentile in 13 patients, and no patient had IGFBP-3 levels>the 95th percentile. Low levels of IGFBP-3 (p=0.002), NIHSS at admission (p=0.043) and age (p=0.001) were associated with unfavourable functional outcome in the univariate analyses. In multivariate analysis including IGFBP-3, IGF-1, age, thrombolysis and NIHSS only low IGFBP-3 levels (OR 7.2, 95%CI 1.8–29.0, p=0.006) were associated with unfavourable functional outcome. If lesion volume was incuded (n=71), only IGFBP-3 levels (OR 7.2, 95%CI 1.5–35.5, p=0.015) were associated with unfavourable functional outcome.

Conclusion: IGFBP-3 levels after ischemic stroke may independently predict functional outcome after one year.

Key words

acute cerebral infarction - neuroprotectors - mRS
 

  • References

  • 1 Aberg D. Role of the growth hormone/insulin-like growth factor 1 axis in neurogenesis. Endocr Dev 2010; 17: 63-76
    PubMedGoogle Scholar
  • 2 Martin JL, Baxter RC. Signalling pathways of insulin-like growth factors (igfs) and igf binding protein-3. Growth Factors 2011; 29: 235-244
    CrossrefPubMedGoogle Scholar
  • 3 Guan J, Bennet L, Gluckman PD et al. Insulin-like growth factor-1 and post-ischemic brain injury. Prog Neurobiol 2003; 70: 443-462
    CrossrefPubMedGoogle Scholar
  • 4 Baxter RC. Characterization of the Acid-Labile Subunit of the Growth Hormone-Dependent Insulin-Like Growth Factor Binding Protein Complex*. J Clin Endocrinol Metab 1988; 67: 265-272
    CrossrefPubMedGoogle Scholar
  • 5 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
    CrossrefPubMedGoogle Scholar
  • 6 Firth SM, Baxter RC. Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev 2002; 23: 824-854
    CrossrefPubMedGoogle Scholar
  • 7 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. Arterioscler Thromb Vasc Biol 2000; 20: E10-15
    CrossrefPubMedGoogle Scholar
  • 8 van den Beld AW, Bots ML, Janssen JA et al. Endogenous hormones and carotid atherosclerosis in elderly men. Am J Epidemiol 2003; 157: 25-31
    CrossrefPubMedGoogle Scholar
  • 9 Kawachi S, Takeda N, Sasaki A et al. Circulating insulin-like growth factor-1 and insulin-like growth factor binding protein-3 are associated with early carotid atherosclerosis. Arterioscler Thromb Vasc Biol 2005; 25: 617-621
    CrossrefPubMedGoogle Scholar
  • 10 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 Endocr Metab 2005; 90: 5937-5941
    CrossrefPubMedGoogle Scholar
  • 11 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 1997; 28: 1744-1748
    CrossrefPubMedGoogle Scholar
  • 12 Bondanelli M, Ambrosio MR, Onofri A et al. Predictive value of circulating insulin-like growth factor i levels in ischemic stroke outcome. J Clin Endocr Metab 2006; 91: 3928-3934
    CrossrefPubMedGoogle Scholar
  • 13 Aberg D, Jood K, Blomstrand C et al. Serum igf-i levels correlate to improvement of functional outcome after ischemic stroke. J Clin Endocr Metab 2011; 96: E1055-1064
    CrossrefPubMedGoogle Scholar
  • 14 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
    CrossrefPubMedGoogle Scholar
  • 15 Endres M, Piriz J, Gertz K et al. Serum insulin-like growth factor i and ischemic brain injury. Brain Res 2007; 1185: 328-335
    CrossrefPubMedGoogle Scholar
  • 16 Ebinger M, Heuschmann PU, Jungehuelsing GJ et al. The berlin ‘cream&sugar’ study: The prognostic impact of an oral triglyceride tolerance test in patients after acute ischaemic stroke. Int J Stroke 2010; 5: 126-130
    CrossrefPubMedGoogle Scholar
  • 17 Janssen PM, Visser NA, Dorhout Mees SM et al. Comparison of telephone and face-to-face assessment of the modified rankin scale. Cerebrovasc Dis 2010; 29: 137-139
    CrossrefPubMedGoogle Scholar
  • 18 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 Me 2004; 42: 654-664
    PubMedGoogle Scholar
  • 19 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. Horm Res 2003; 60: 53-60
    CrossrefPubMedGoogle Scholar
  • 20 Lee YC, Jogie-Brahim S, Lee DY et al. Insulin-like growth factor-binding protein-3 (IGFBP-3) blocks the effects of asthma by negatively regulating NF-κB signaling through IGFBP-3 R-mediated activation of caspases. J Biol Chem 2011; 286: 17898-17909
    CrossrefPubMedGoogle Scholar
  • 21 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 Endocr Metab 1994; 79: 1871-1876
    PubMedGoogle Scholar
  • 22 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 2009; 40: e83-e88
    CrossrefPubMedGoogle Scholar
  • 23 Boehncke S, Ackermann H, Badenhoop K et al. Pituitary function and igf-i levels following ischemic stroke. Cerebrovasc Dis 2011; 31: 163-169
    CrossrefPubMedGoogle Scholar
  • 24 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
    CrossrefPubMedGoogle Scholar
  • 25 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
    CrossrefPubMedGoogle Scholar
  • 26 Duron E, Vidal JS, Funalot B et al. Insulin-Like Growth Factor I, Insulin-like Growth factor Binding Protein 3, and Atrial Fibrillation in the Elderly. Gerontol A Biol Sci Med Sci 2013; DOI: 10.1093/gerona/glt206.
    PubMedGoogle Scholar
  • 27 Duron E, Vidal JS, Funalot B et al. Insulin-Like Growth Factor-I, Insulin-Like Growth factor Binding Protein-3 and Blood Hemoglobin Concentration in an Elderly Population. Gerontol A Biol Sci Med Sci 2014; DOI: 10.1093/gerona/glu200.
    PubMedGoogle Scholar
  • 28 Silva-Couto MD, Prado-Medeiros CL, Oliveira AB et al. Muscle Atrophy, Voluntary Activation Disturbances, and Low Concentrations of IGF-1 and IGFBP-3 Are Associated With Weakness in People With Chronic Stroke. Phy Ther 2014; 94: 957-967
    PubMedGoogle Scholar
  • 29 Beilharz EJ, Russo VC, Butler G 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: 119-134
    CrossrefPubMedGoogle Scholar
  • 30 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 2006; 37: 2368-2371
    CrossrefPubMedGoogle Scholar
  • 31 Giovannini S, Cesari M, Marzetti E et al. Effects of ace-inhibition on igf-1 and igfbp-3 concentrations in older adults with high cardiovascular risk profile. J Nutr Health Aging 2010; 14: 457-460
    CrossrefPubMedGoogle Scholar
  • 32 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 Endocr Metab 2010; 95: 2113-2122
    CrossrefPubMedGoogle Scholar
  • 33 Lin IH, Ho ML, Chen HY et al. Smoking, green tea consumption, genetic polymorphisms in the insulin-like growth factors and lung cancer risk. PLoS One 2012; 7: e30951
    CrossrefPubMedGoogle Scholar
  • 34 Kaklamani VG, Linos A, Kaklamani E et al. Age, sex, and smoking are predictors of circulating insulin-like growth factor 1 and insulin-like growth factor-binding protein 3. J Clin Oncol 1999; 17: 813-817
    PubMedGoogle Scholar
  • 35 Yu H, Spitz MR, Mistry J et al. Plasma levels of insulin-like growth factor-i and lung cancer risk: A case-control analysis. J Natl Cancer Inst 1999; 91: 151-156
    CrossrefPubMedGoogle Scholar
  • 36 Alberti KG, Zimmet P, Shaw J. The metabolic syndrome – a new worldwide definition. Lancet 2005; 366: 1059-1062
    CrossrefPubMedGoogle Scholar