Inflammation

, Volume 35, Issue 2, pp 723–729

Timing of Insulin Therapy Affects the Inflammatory Response in Endotoxemic Rats

  • Bo Zou
  • Qiyi Chen
  • Shaoqiu Tang
  • Tao Gao
  • Juanjuan Zhang
  • Fengchan Xi
  • Wenkui Yu
Article

Abstract

The aim of the present study was to determine whether timing of insulin administration influences the hepatic and serum proinflammatory and anti-inflammatory cytokines during endotoxemia stimulated by lipopolysaccharide (LPS). Eighty-one male Sprague–Dawley rats were divided into different time groups and insulin was given 30 min pre-LPS administration or hour 0, 1, 3, 6, 12, 24 after the induction of endotoxemia, respectively. Hepatic and serum proinflammatory cytokines IL-1β, IL-6, and TNF-α, and anti-inflammatory cytokine IL-10 were detected 24 and 48 h after the induction of endotoxemia. Compared with sham control rats, serum concentrations of proinflammatory cytokines IL-1β, IL-6, and TNF-α and anti-inflammatory cytokine IL-10 significantly increased on 24 and 48 h after induction of endotoxemia. Similarly, LPS administration also significantly increased the hepatic IL-1β, TNF-α, IL-6, and IL-10 protein concentration 48 h after LPS injection. Compared with levels in positive LPS controls animals receiving saline, on 24 and 48 h after LPS injection, insulin administrated ahead of 6 h after LPS injection significantly decreased the serum IL-1β, IL-6, and TNF-a concentration (P < 0.05), and significantly increased anti-inflammatory cytokine IL-10 concentration (P < 0.05); hepatic IL-1β and IL-6 expression were (P < 0.05) significantly decreased compared with levels in positive LPS controls. But, the significant decrease of hepatic TNF-a expression and significant increase of hepatic IL-10 were only seen in the animals in which insulin was administrated at 30 min pre-LPS or coadministrated with LPS. Insulin administrated 6 h after LPS injection lost the ability to significantly reduce serum or hepatic IL-1β, TNF-α, and IL-6 concentrations. Insulin has a protective role in systemic inflammatory response syndrome related to sepsis, such as downregulation of proinflammatory cytokines and upregulation of anti-inflammatory cytokine production. However, timing of insulin administrated may change its effect of inflammatory response in endotoxemic rats. Insulin administrated 6 h after LPS injection weaken the ability to protect inflammatory response related to sepsis.

KEY WORDS

insulin endotoxin proinflammatory cytokine anti-inflammatory cytokine timing of therapy 

References

  1. 1.
    van den Berghe, G., et al. 2001. Intensive insulin therapy in the critically ill patients. The New England Journal of Medicine 345(19): 1359–1367.PubMedCrossRefGoogle Scholar
  2. 2.
    Van den Berghe, G., et al. 2006. Intensive insulin therapy in the medical ICU. The New England Journal of Medicine 354(5): 449–461.PubMedCrossRefGoogle Scholar
  3. 3.
    Brunkhorst, F.M., et al. 2008. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. The New England Journal of Medicine 358(2): 125–139.PubMedCrossRefGoogle Scholar
  4. 4.
    Finfer, S., et al. 2009. Intensive versus conventional glucose control in critically ill patients. The New England Journal of Medicine 360(13): 1283–1297.PubMedCrossRefGoogle Scholar
  5. 5.
    Viardot, A., et al. 2007. Potential antiinflammatory role of insulin via the preferential polarization of effector T cells toward a T helper 2 phenotype. Endocrinology 148(1): 346–353.PubMedCrossRefGoogle Scholar
  6. 6.
    Jeschke, M.G., et al. 2004. Insulin attenuates the systemic inflammatory response in endotoxemic rats. Endocrinology 145(9): 4084–4093.PubMedCrossRefGoogle Scholar
  7. 7.
    Honiden, S., et al. 2008. Early versus late intravenous insulin administration in critically ill patients. Intensive Care Medicine 34(5): 881–887.PubMedCrossRefGoogle Scholar
  8. 8.
    Langouche, L., et al. 2007. Effect of intensive insulin therapy on insulin sensitivity in the critically ill. Journal of Clinical Endocrinology and Metabolism 92(10): 3890–3897.PubMedCrossRefGoogle Scholar
  9. 9.
    Osuchowski, M., et al. 2006. Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality. The Journal of Immunology 177(3): 1967.PubMedGoogle Scholar
  10. 10.
    Van den Berghe, G., et al. 2003. Outcome benefit of intensive insulin therapy in the critically ill: Insulin dose versus glycemic control. Critical Care Medicine 31(2): 359–366.PubMedCrossRefGoogle Scholar
  11. 11.
    Zanotti, S., and A. Kumar. 2002. Cytokine modulation in sepsis and septic shock. Expert Opinion on Investigational Drugs 11(8): 1061.PubMedCrossRefGoogle Scholar
  12. 12.
    Casey, L., R. Balk, and R. Bone. 1993. Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome. Annals of Internal Medicine 119(8): 771.PubMedGoogle Scholar
  13. 13.
    Jeschke, M.G., et al. 2005. Insulin prevents liver damage and preserves liver function in lipopolysaccharide-induced endotoxemic rats. Journal of Hepatology 42(6): 870–879.PubMedCrossRefGoogle Scholar
  14. 14.
    Frink, M., et al. 2009. IL-6 predicts organ dysfunction and mortality in patients with multiple injuries. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine 17: 49.PubMedCrossRefGoogle Scholar
  15. 15.
    Rau, S., et al. 2007. Plasma interleukin 6 response is predictive for severity and mortality in canine systemic inflammatory response syndrome and sepsis. Veterinary Clinical Pathology 36(3): 253–260.PubMedCrossRefGoogle Scholar
  16. 16.
    Barkhausen, T., et al. 2009. Insulin therapy induces changes in the inflammatory response in a murine 2-hit model. Injury 40(8): 806–814.PubMedCrossRefGoogle Scholar
  17. 17.
    Debets, J., and R. Kampmeijer. 1989. Plasma tumor necrosis factor and mortality in critically ill septic patients. Critical Care Medicine 17(6): 489.PubMedCrossRefGoogle Scholar
  18. 18.
    Leonidou, L., et al. 2007. Cytokine production and hospital mortality in patients with sepsis-induced stress hyperglycemia. Journal of Infection 55(4): 340–346.PubMedCrossRefGoogle Scholar
  19. 19.
    de Luca, C., and J. Olefsky. 2008. Inflammation and insulin resistance. FEBS Letters 582(1): 97–105.PubMedCrossRefGoogle Scholar
  20. 20.
    Fram, R., et al. 2010. Intensive insulin therapy improves insulin sensitivity and mitochondrial function in severely burned children*. Critical Care Medicine 38(6): 1475.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Bo Zou
    • 1
  • Qiyi Chen
    • 1
  • Shaoqiu Tang
    • 1
  • Tao Gao
    • 2
  • Juanjuan Zhang
    • 2
  • Fengchan Xi
    • 2
  • Wenkui Yu
    • 2
  1. 1.Medical School of Nanjing UniversityNanjingChina
  2. 2.Research Institute of General SurgeryNanjing General Hospital of Nanjing Military CommandNanjingChina

Personalised recommendations