Acute Hyperglycemia Worsens Hepatic Ischemia/Reperfusion Injury in Rats
Acute hyperglycemia is known to worsen ischemia/reperfusion (I/R) injury following myocardial infarction and stroke. We investigated whether acute hyperglycemia worsens injury and amplifies the inflammatory response evoked by hepatic I/R.
Rats were pretreated with an intraperitoneal injection of 25% glucose or 0.9% sodium chloride (10 ml/kg BW). Subsequently, rats underwent partial (70%) hepatic ischemia for 45 min. After 4 h of reperfusion, hepatic injury, oxidative stress, inflammation, and heat shock protein expression were assessed.
Liver injury was increased in the hyperglycemic group with alanine aminotransferase (ALT) and aspartate aminotransferease (AST) serum concentrations of 7,832 ± 3,374 and 10,677 ± 4,110 U/L compared to 3,245 ± 2,009 and 5,386 ± 3,393 U/L (p < 0.05 vs. control). Hyperglycemic I/R was associated with increased liver nitrotyrosine concentrations and increased neutrophil infiltration. I/R upregulated the protective heat shock proteins HSP32 and HSP70 in control animals, but this protective mechanism was inhibited by hyperglycemia: HSP32 expression decreased from 1.97 ± 0.89 (control) to 0.46 ± 0.13 (hyperglycemia), HSP70 expression decreased from 18.99 ± 11.55 (control) to 3.22 ± 0.56 (hyperglycemia), (expression normalized to sham, both p < 0.05 vs. control I/R).
Acute hyperglycemia worsens hepatic I/R injury by amplifying oxidative stress and the inflammatory response to I/R. The increase in injury is associated with a downregulation of the protective heat shock proteins HSP32 and HSP70.
- Doenst T, Wijeysundera D, Karkouti K, Zechner C, Maganti M, Rao V, Borger MA. Hyperglycemia during cardiopulmonary bypass is an independent risk factor for mortality in patients undergoing cardiac surgery. J Thorac Cardiovasc Surg 2005;130:1144. CrossRef
- Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM, Kitabchi AE. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab 2002;87:978–982. CrossRef
- van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001;345:1359–1367. CrossRef
- Van den Berghe G, Wouters PJ, Bouillon R, Weekers F, Verwaest C, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P. Outcome benefit of intensive insulin therapy in the critically ill: Insulin dose versus glycemic control. Crit Care Med 2003;31:359–366. CrossRef
- Ellger B, Debaveye Y, Vanhorebeek I, Langouche L, Giulietti A, Van Etten E, Herijgers P, Mathieu C, Van den Berghe G. Survival benefits of intensive insulin therapy in critical illness: impact of maintaining normoglycemia versus glycemia-independent actions of insulin. Diabetes 2006;55:1096–1105. CrossRef
- Martin A, Rojas S, Chamorro A, Falcon C, Bargallo N, Planas AM. Why does acute hyperglycemia worsen the outcome of transient focal cerebral ischemia? Role of corticosteroids, inflammation, and protein O-glycosylation. Stroke 2006;37:1288–1295. CrossRef
- Hirose R, Xu F, Dang K, Liu T, Behrends M, Brakeman PR, Wiener-Kronish J, Niemann CU. Transient hyperglycemia affects the extent of ischemia–reperfusion-induced renal injury in rats. Anesthesiology 2008;108:402–414. CrossRef
- Ling PR, Mueller C, Smith RJ, Bistrian BR. Hyperglycemia induced by glucose infusion causes hepatic oxidative stress and systemic inflammation, but not STAT3 or MAP kinase activation in liver in rats. Metabolism 2003;52:868–874. CrossRef
- Iwasaki Y, Kambayashi M, Asai M, Yoshida M, Nigawara T, Hashimoto K. High glucose alone, as well as in combination with proinflammatory cytokines, stimulates nuclear factor kappa-B-mediated transcription in hepatocytes in vitro. J Diabetes Complications 2007;21:56–62. CrossRef
- Giugliano D, Marfella R, Coppola L, Verrazzo G, Acampora R, Giunta R, Nappo F, Lucarelli C, D’Onofrio F. Vascular effects of acute hyperglycemia in humans are reversed by L-arginine. Evidence for reduced availability of nitric oxide during hyperglycemia. Circulation 1997;95:1783–1790.
- Rogers H 3rd, Zibari GB, Roberts J, Turnage R, Lefer DJ. Nitric oxide attenuates ischaemia–reperfusion (I/R) injury in the diabetic liver. Clin Transplant 2004;18(Suppl 12):7–11. CrossRef
- Elrod JW, Duranski MR, Langston W, Greer JJ, Tao L, Dugas TR, Kevil CG, Champion HC, Lefer DJ. eNOS gene therapy exacerbates hepatic ischemia–reperfusion injury in diabetes: a role for eNOS uncoupling. Circ Res 2006;99:78–85. CrossRef
- Suzuki S, Nakamura S, Koizumi T, Sakaguchi S, Baba S, Muro H, Fujise Y. The beneficial effect of a prostaglandin I2 analog on ischemic rat liver. Transplantation 1991;52:979–983. CrossRef
- Saraste A. Morphologic criteria and detection of apoptosis. Herz 1999;24:189–195. CrossRef
- Kohli V, Selzner M, Madden JF, Bentley RC, Clavien PA. Endothelial cell and hepatocyte deaths occur by apoptosis after ischemia–reperfusion injury in the rat liver. Transplantation 1999;67:1099–1105. CrossRef
- Gujral JS, Bucci TJ, Farhood A, Jaeschke H. Mechanism of cell death during warm hepatic ischemia–reperfusion in rats: apoptosis or necrosis? Hepatology 2001;33:397–405. CrossRef
- Jaeschke H, Lemasters JJ. Apoptosis versus oncotic necrosis in hepatic ischemia/reperfusion injury. Gastroenterology 2003;125:1246–1257. CrossRef
- Brix-Christensen V, Gjedsted J, Andersen SK, Vestergaard C, Nielsen J, Rix T, Nyboe R, Andersen NT, Larsson A, Schmitz O, Tonnesen E. Inflammatory response during hyperglycemia and hyperinsulinemia in a porcine endotoxemic model: the contribution of essential organs. Acta Anaesthesiol Scand 2005;49:991–998. CrossRef
- Raina AK, Perry G, Nunomura A, Sayre LM, Smith MA. Histochemical and immunocytochemical approaches to the study of oxidative stress. Clin Chem Lab Med 2000;38:93–97. CrossRef
- Jaeschke H, Farhood A. Neutrophil and Kupffer cell-induced oxidant stress and ischemia–reperfusion injury in rat liver. Am J Physiol 1991;260:G355–362.
- Ling PR, Smith RJ, Bistrian BR. Hyperglycemia enhances the cytokine production and oxidative responses to a low but not high dose of endotoxin in rats. Crit Care Med 2005;33:1084–1089. CrossRef
- Muranyi M, He QP, Fong KS, Li PA. Induction of heat shock proteins by hyperglycemic cerebral ischemia. Brain Res Mol Brain Res 2005;139:80–87. CrossRef
- Yamagishi N, Nakayama K, Wakatsuki T, Hatayama T. Characteristic changes of stress protein expression in streptozotocin-induced diabetic rats. Life Sci 2001;69:2603–2609. CrossRef
- Najemnikova E, Rodgers CD, Locke M. Altered heat stress response following streptozotocin-induced diabetes. Cell Stress Chaperones 2007;12:342–352. CrossRef
- Swiecki C, Stojadinovic A, Anderson J, Zhao A, Dawson H, Shea-Donohue T. Effect of hyperglycemia and nitric oxide synthase inhibition on heat tolerance and induction of heat shock protein 72 kDa in vivo. Am Surg 2003;69:587–592.
- Santoro MG. Heat shock factors and the control of the stress response. Biochem Pharmacol 2000;59:55–63. CrossRef
- Hooper PL. Insulin signaling, GSK-3, heat shock proteins and the natural history of type 2 diabetes mellitus: a hypothesis. Metab Syndr Relat Disord 2007;5:220–230. CrossRef
- Kavanagh K, Zhang L, Wagner JD. Tissue-specific regulation and expression of heat shock proteins in type 2 diabetic monkeys. Cell Stress Chaperones 2009;14:291–299. CrossRef
- Acute Hyperglycemia Worsens Hepatic Ischemia/Reperfusion Injury in Rats
- Open Access
- Available under Open Access This content is freely available online to anyone, anywhere at any time.
Journal of Gastrointestinal Surgery
Volume 14, Issue 3 , pp 528-535
- Cover Date
- Print ISSN
- Online ISSN
- Additional Links
- Inflammatory response
- Industry Sectors
- Author Affiliations
- 1. Department of Anesthesia and Perioperative Care, University of California San Francisco, 533 Parnassus Avenue, U 368n, San Francisco, CA, 94143-0648, USA
- 2. Servicio de Anestesiologia, Hospital Clinic de Barcelona, Universitat de Barcelona, Barcelona, Spain
- 3. Department of Surgery, Division of Transplantation, University of California San Francisco, San Francisco, CA, USA
- 4. Department of Pathology, University of California San Francisco, San Francisco, CA, USA