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Molecular Medicine

, Volume 17, Issue 5–6, pp 516–522 | Cite as

Insulin Protects against Hepatic Damage Postburn

  • Marc G Jeschke
  • Robert Kraft
  • Juquan Song
  • Gerd G Gauglitz
  • Robert A Cox
  • Natasha C Brooks
  • Celeste C Finnerty
  • Gabriela A Kulp
  • David N Herndon
  • Darren Boehning
Research Article

Abstract

Burn injury causes hepatic dysfunction associated with endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR). ER stress/UPR leads to hepatic apoptosis and activation of the Jun-N-terminal kinase (JNK) signaling pathway leading to vast metabolic alterations. Insulin has been shown to attenuate hepatic damage and to improve liver function. We therefore hypothesized that insulin administration exerts its effects by attenuating postburn hepatic ER stress and subsequent apoptosis. Male Sprague Dawley rats received a 60% total body surface area (TBSA) burn injury. Animals were randomized to receive saline (controls) or insulin (2.5 IU/kg q. 24 h) and euthanized at 24 and 48 h postburn. Burn injury induced dramatic changes in liver structure and function, including induction of the ER stress response, mitochondrial dysfunction, hepatocyte apoptosis, and up-regulation of inflammatory mediators. Insulin decreased hepatocyte caspase-3 activation and apoptosis significantly at 24 and 48 h postburn. Furthermore, insulin administration decreased ER stress significantly and reversed structural and functional changes in hepatocyte mitochondria. Finally, insulin attenuated the expression of inflammatory mediators IL-6, MCP-1, and CINC-1. Insulin alleviates burn-induced ER stress, hepatocyte apoptosis, mitochondrial abnormalities, and inflammation leading to improved hepatic structure and function significantly. These results support the use of insulin therapy after traumatic injury to improve patient outcomes.

Notes

Acknowledgments

The authors wish to thank Hal K Hawkins for assistance with the transmission electron microscopy. We also like to thank Eileen Figueroa and Steven Schuenke for their assistance in editing the manuscript. This work was supported by the Shriners Hospitals for Children grants 8660 (MG Jeschke), 8640 (MG Jeschke), 8760 (DN Herndon), 9145 (DN Herndon), and National Institutes of Health grants GM081685 (DB Boehning), GM008256 (DN Herndon), R01 GM087285 (MG Jeschke) and GM60338 (DN Herndon).

References

  1. 1.
    Bringham PA, McLoughlin E. (1996) Burn incidence and medical care use in the United States: estimates, trends and data sources. J. Burn Care Rehabil. 17:95–107.CrossRefGoogle Scholar
  2. 2.
    Jeschke MG, et al. (2001) Cell proliferation, apoptosis, NF-kappaB expression, enzyme, protein, and weight changes in livers of burned rats. Am. J. Physiol. Gastrointest. Liver Physiol. 280:G1314–20.CrossRefGoogle Scholar
  3. 3.
    Jeschke MG, Mlcak RP, Finnerty CC, Herndon DN. (2007) Changes in liver function and size after a severe thermal injury. Shock. 28:172–7.CrossRefGoogle Scholar
  4. 4.
    Jeschke MG, et al. (2005) Insulin prevents liver damage and preserves liver function in lipopolysaccharide-induced endotoxemic rats. J. Hepatol. 42:870–9.CrossRefGoogle Scholar
  5. 5.
    Klein D, Schubert T, Horch RE, Jauch KW, Jeschke MG. (2004) Insulin treatment improves hepatic morphology and function through modulation of hepatic signals after severe trauma. Ann. Surg. 240:340–9.CrossRefGoogle Scholar
  6. 6.
    Moshage H. (1997) Cytokines and the hepatic acute phase response. J. Pathol. 181:257–66.CrossRefGoogle Scholar
  7. 7.
    Jeschke MG. (2009) The hepatic response to thermal injury: is the liver important for postburn outcomes? Mol. Med. 15:337–51.CrossRefGoogle Scholar
  8. 8.
    Price LA, Thombs B, Chen CL, Milner SM. (2007) Liver disease in burn injury: evidence from a national sample of 31,338 adult patients. J. Burns Wounds. 7:e1.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Jeschke MG, Barrow RE, Herndon DN. (2004) Extended hypermetabolic response of the liver in severely burned pediatric patients. Arch. Surg. 139:641–7.CrossRefGoogle Scholar
  10. 10.
    Jeschke MG, Boehning DF, Finnerty CC, Herndon DN. (2007) Effect of insulin on the inflammatory and acute phase response after burn injury. Crit. Care Med. 35:S519–23.CrossRefGoogle Scholar
  11. 11.
    Jeschke MG, et al. (2009) Calcium and ER stress mediate hepatic apoptosis after burn injury. J. Cell Mol. Med. 13:1857–65.CrossRefGoogle Scholar
  12. 12.
    Jeschke MG, et al. (2008) Pathophysiologic response to severe burn injury. Ann. Surg. 248:387–401.CrossRefGoogle Scholar
  13. 13.
    Van den Berghe G, et al. (2006) Intensive insulin therapy in the medical ICU. N. Engl. J. Med. 354:449–61.CrossRefGoogle Scholar
  14. 14.
    van den Berghe G, et al. (2001) Intensive insulin therapy in the critically ill patients. N. Engl. J. Med. 345:1359–67.CrossRefGoogle Scholar
  15. 15.
    Jeschke MG, Klein D, Herndon DN. (2004) Insulin treatment improves the systemic inflammatory reaction to severe trauma. Ann. Surg. 239:553–60.CrossRefGoogle Scholar
  16. 16.
    Jeschke MG, et al. (2010) Intensive insulin therapy in severely burned pediatric patients: a prospective randomized trial. Am. J. Respir. Crit. Care Med. 182:351–9.CrossRefGoogle Scholar
  17. 17.
    Jeschke MG, Einspanier R, Klein D, Jauch KW. (2002) Insulin attenuates the systemic inflammatory response to thermal trauma. Mol. Med. 8:443–50.CrossRefGoogle Scholar
  18. 18.
    Herndon DN, Wilmore DW, Mason AD Jr. (1978) Development and analysis of a small animal model simulating the human postburn hypermetabolic response. J. Surg. Res. 25:394–403.CrossRefGoogle Scholar
  19. 19.
    Gauglitz GG, et al. (2009) Post-burn hepatic insulin resistance is associated with ER stress. Shock. 2009, June 18 [Epub ahead of print].Google Scholar
  20. 20.
    Boehning D, et al. (2003) Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis. Nat. Cell Biol. 5:1051–61.CrossRefGoogle Scholar
  21. 21.
    Boehning D, Patterson RL, Snyder SH. (2004) Apoptosis and calcium: new roles for cytochrome c and inositol 1,4,5-trisphosphate. Cell Cycle. 3:252–254.CrossRefGoogle Scholar
  22. 22.
    Boehning D, van Rossum DB, Patterson RL, Snyder SH. (2005) A peptide inhibitor of cytochrome c/inositol 1,4,5-trisphosphate receptor binding blocks intrinsic and extrinsic cell death pathways. Proc. Natl. Acad. Sci. U. S. A. 102:1466–71.CrossRefGoogle Scholar
  23. 23.
    Wozniak AL, et al. (2006) Requirement of biphasic calcium release from the endoplasmic reticulum for Fas-mediated apoptosis. J. Cell Biol. 175:709–14.CrossRefGoogle Scholar
  24. 24.
    Song J, Finnerty CC, Herndon DN, Boehning D, Jeschke MG. (2009) Severe burn-induced endoplasmic reticulum stress and hepatic damage in mice. Mol. Med. 15:316–20.CrossRefGoogle Scholar
  25. 25.
    Hemmila MR, Taddonio MA, Arbabi S, Maggio PM, Wahl WL. (2008) Intensive insulin therapy is associated with reduced infectious complications in burn patients. Surgery. 144:629–37.CrossRefGoogle Scholar
  26. 26.
    Gauglitz GG, et al. (2009) Insulin increases resistance to burn wound infection-associated sepsis. Crit. Care Med. 38:202–8.CrossRefGoogle Scholar
  27. 27.
    Ron D, Walter P. (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol. Cell. Biol. 8:519–29.CrossRefGoogle Scholar
  28. 28.
    Hampton RY. (2000) ER stress response: getting the UPR hand on misfolded proteins. Curr. Biol. 10:R518–21.CrossRefGoogle Scholar
  29. 29.
    Mori K. (2000) Tripartite management of unfolded proteins in the endoplasmic reticulum. Cell. 101:451–4.CrossRefGoogle Scholar
  30. 30.
    Ozcan U, et al. (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 306:457–61.CrossRefGoogle Scholar
  31. 31.
    Ozcan U, et al. (2006) Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 313:1137–40.CrossRefGoogle Scholar
  32. 32.
    White MF. (1997) The insulin signalling system and the IRS proteins. Diabetologia. 40 Suppl 2:S2–17.CrossRefGoogle Scholar
  33. 33.
    Kahn CR, et al. (1993) The insulin receptor and its substrate: molecular determinants of early events in insulin action. Recent Prog. Horm. Res. 48:291–339.CrossRefGoogle Scholar
  34. 34.
    Le Roith D, Zick Y. (2001) Recent advances in our understanding of insulin action and insulin resistance. Diabetes Care. 24:588–97.CrossRefGoogle Scholar
  35. 35.
    Gauglitz GG, Herndon DN, Jeschke MG. (2008) Insulin resistance postburn: underlying mechanisms and current therapeutic strategies. J. Burn Care Res. 29:683–94.CrossRefGoogle Scholar
  36. 36.
    Aguirre V, Uchida T, Yenush L, Davis R, White MF. (2000) The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). J. Biol. Chem. 275:9047–54.CrossRefGoogle Scholar

Copyright information

© The Feinstein Institute for Medical Research 2011

Authors and Affiliations

  • Marc G Jeschke
    • 1
    • 2
    • 3
    • 5
  • Robert Kraft
    • 1
    • 2
  • Juquan Song
    • 1
    • 2
  • Gerd G Gauglitz
    • 1
    • 6
  • Robert A Cox
    • 1
  • Natasha C Brooks
    • 3
  • Celeste C Finnerty
    • 1
    • 2
  • Gabriela A Kulp
    • 1
  • David N Herndon
    • 1
    • 2
  • Darren Boehning
    • 4
  1. 1.Shriners Hospitals for ChildrenThe University of Texas Medical BranchGalvestonUSA
  2. 2.Department of SurgeryThe University of Texas Medical BranchGalvestonUSA
  3. 3.Department of Biochemistry and Molecular BiologyThe University of Texas Medical BranchGalvestonUSA
  4. 4.Department of Neuroscience and Cell BiologyThe University of Texas Medical BranchGalvestonUSA
  5. 5.Director Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Department of Surgery Division of Plastic SurgeryUniversity of Toronto Senior Scientist Sunnybrook Research InstituteTorontoCanada
  6. 6.Department of DermatologyLudwig-Maximilians University of MunichMunichGermany

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