Molecular Medicine

, Volume 19, Issue 1, pp 1–6 | Cite as

Effects of Metformin on Burn-Induced Hepatic Endoplasmic Reticulum Stress in Male Rats

  • Yaeko Hiyama
  • Alexandra H. Marshall
  • Robert Kraft
  • Nour Qa’aty
  • Anna Arno
  • David N. Herndon
  • Marc G. Jeschke
Research Article


Severe burn injury causes hepatic dysfunction that results in major metabolic derangements including insulin resistance and hyperglycemia and is associated with hepatic endoplasmic reticulum (ER) stress. We have recently shown that insulin reduces ER stress and improves liver function and morphology; however, it is not clear whether these changes are directly insulin mediated or are due to glucose alterations. Metformin is an antidiabetic agent that decreases hyperglycemia by different pathways than insulin; therefore, we asked whether metformin affects postburn ER stress and hepatic metabolism. The aim of the present study is to determine the effects of metformin on postburn hepatic ER stress and metabolic markers. Male rats were randomized to sham, burn injury and burn injury plus metformin and were sacrificed at various time points. Outcomes measured were hepatic damage, function, metabolism and ER stress. Burn-induced decrease in albumin mRNA and increase in alanine transaminase (p < 0.01 versus sham) were not normalized by metformin treatment. In addition, ER stress markers were similarly increased in burn injury with or without metformin compared with sham (p < 0.05). We also found that gluconeogenesis and fatty acid metabolism gene expressions were upregulated with or without metformin compared with sham (p < 0.05). Our results indicate that, whereas thermal injury results in hepatic ER stress, metformin does not ameliorate postburn stress responses by correcting hepatic ER stress.



This research was supported by the National Institutes of Health (R01-GM087285-01 to MG Jeschke), Canadian Institutes of Health Research (123336), the CFI’s Leader’s Opportunity Fund (25407 to MG Jeschke) and the Health Research Grant Program from the Physicians’ Services Incorporated Foundation (to MG Jeschke). We thank the SRI Genomics Core Facility for genotyping the samples.


  1. 1.
    Jeschke MG, et al. (2011) Long-term persistence of the pathophysiologic response to severe burn injury. PLoS One. 6:e21245.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Jeschke MG, et al. (2008) Pathophysiologic response to severe burn injury. Ann. Surg. 248:387–401.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Jeschke MG, Micak 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. (2009) The hepatic response to thermal injury: is the liver important for post-burn outcomes? Mol. Med. 15:337–51.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Jeschke MG, Barrow RE, Herndon DN. (2004) Extended hypermetabolic response of the liver in severely burned pediatric patients. Arch. Surg. 139:641–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Jeschke MG, et al. (2011) Insulin protects against hepatic damage post-burn. Mol. Med. 17:516–22.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Gore DC, Wolf SE, Herndon DN, Wolfe RR. (2003) Metformin blunts stress-induced hyperglycemia after thermal injury. J. Trauma. 54:555–61.CrossRefPubMedGoogle Scholar
  9. 9.
    Frayn KN. (1976) Effects of metformin on insulin resistance after injury in the rat. Diabetologia. 12:53–60.CrossRefPubMedGoogle Scholar
  10. 10.
    Zhou G, et al. (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108:1167–74.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Shaw RJ, et al. (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 310:1642–6.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Towler MC, Hardie DG. (2007) AMP-activated protein kinase in metabolic control and insulin signaling. Circ. Res. 100:328–41.CrossRefPubMedGoogle Scholar
  13. 13.
    Argaud D, Roth H, Wiernsperger N, Leverve XM. (1993) Metformin decreases gluconeogenesis by enhancing the pyruvate kinase flux in isolated rat hepatocytes. Eur. J. Biochem. 213:1341–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Otto M, Breinholt J, Westergaard N. (2003) Metformin inhibits glycogen synthesis and gluconeogenesis in cultured rat hepatocytes. Diabetes Obes. Metab. 5:189–94.CrossRefPubMedGoogle Scholar
  15. 15.
    Kim YD, et al. (2008) Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase-dependent regulation of the orphan nuclear receptor SHP. Diabetes. 57:306–14.CrossRefPubMedGoogle Scholar
  16. 16.
    Yoshida T, et al. (2009) Metformin primarily decreases plasma glucose not by gluconeogenesis suppression but by activating glucose utilization in a non-obese type 2 diabetes Goto-Kakizaki rats. Eur. J. Pharmacol. 623:141–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Lin HZ, et al. (2000) Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat. Med. 6:998–1003.CrossRefPubMedGoogle Scholar
  18. 18.
    Herndon DN, Wilmore DW, Mason AD Jr. (1978) Development and analysis of a small animal model simulating the human post-burn hypermetabolic response. J. Surg. Res. 25:394–403.CrossRefPubMedGoogle Scholar
  19. 19.
    Folch J, Lees M, Sloane Stanley GH. (1957) A simple method for the isolation and purification of total lipides from animal tissues. J. Biol. Chem. 226:497–509.PubMedGoogle Scholar
  20. 20.
    Warden SM, et al. (2001) Post-translational modifications of the beta-1 subunit of AMP-activated protein kinase affect enzyme activity and cellular localization. Biochem. J. 354:275–83.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Leffler M, et al. (2007) Insulin attenuates apoptosis and exerts anti-inflammatory effects in endotoxemic human macrophages. J. Surg. Res. 143:398–406.CrossRefPubMedGoogle Scholar
  22. 22.
    Eurich DT, et al. (2007) Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. BMJ. 335:497.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Ron D, Walter P. (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell. Biol. 8:519–29.CrossRefGoogle Scholar
  24. 24.
    Liu J, et al. (2010) Endoplasmic reticulum stress involved in the course of lipogenesis in fatty acids-induced hepatic steatosis. J. Gastroenterol. Hepatol. 25:613–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Yeh CH, Chen TP, Wang YC, Lin YM, Fang SW. (2010) AMP-activated protein kinase activation during cardioplegia-induced hypoxia/reoxygenation injury attenuates cardiomyocytic apoptosis via reduction of endoplasmic reticulum stress. Mediators Inflamm. 2010:130636.CrossRefPubMedGoogle Scholar
  26. 26.
    Quentin T, Steinmetz M, Poppe A, Thoms S. (2012) Metformin differentially activates ER stress signaling pathways without inducing apoptosis. Dis. Model Mech. 5:259–69.CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  • Yaeko Hiyama
    • 1
    • 2
  • Alexandra H. Marshall
    • 1
    • 2
  • Robert Kraft
    • 3
  • Nour Qa’aty
    • 1
    • 2
  • Anna Arno
    • 1
    • 2
  • David N. Herndon
    • 4
    • 5
  • Marc G. Jeschke
    • 1
    • 2
  1. 1.Ross Tilley Burn Centre, Sunnybrook Health Sciences CentreSunnybrook Research InstituteTorontoCanada
  2. 2.Department of Surgery, Division of Plastic Surgery, Department of ImmunologyUniversity of TorontoTorontoCanada
  3. 3.Department of TraumaKlinikum MemmingenMemmingenGermany
  4. 4.Shriners Hospitals for ChildrenGalvestonUSA
  5. 5.Department of SurgeryUniversity of Texas Medical BranchGalvestonUSA

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