Vanhorebeek, Ilse, Ellger, Bjoern, De Vos, Rita, Boussemaere, Magaly, Debaveye, Yves, Vander Perre, Sarah, Rabbani, Naila, Thornalley, Paul J. and Van den Berghe, Greet. (2009) Tissue-specific glucose toxicity induces mitochondrial damage in a burn injury model of critical illness. Critical Care Medicine, Vol.37 (No.4). pp. 1355-1364. ISSN 0090-3493

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Abstract

Objective: In critically ill patients, preventing hyperglycemia (HG) with insulin therapy partially prevented organ dysfunction and protected mitochondria. A study in a rabbit model of critical Illness indicated that lower blood glucose level, rather than higher insulinemia, is a key factor in such organ protection. In this model, we now Investigated the Impact of blood glucose lowering vs. hyperinsulinemia (HI) on mitochondria in relation to organ damage. We assessed whether such effects on mitochondria are mediated indirectly via organ perfusion or directly via reducing cellular glucose toxicity.

Design: Prospective, randomized laboratory investigation.

Setting: University laboratory.

Subjects: Three-month-old male rabbits.

Interventions. After induction of critical illness by burn injury, followed by fluid-resuscitation and parenteral nutrition, rabbits were allocated to four groups, each a combination of normal or elevated blood glucose levels with normal or elevated insulin levels. This required alloxan administration, immediately followed by intravenous insulin and glucose infusions titrated to the respective targets.

Measurements and Main Results. In liver, the reduced damage by glucose lowering was not explained by better perfusion/oxygen delivery. Abnormal mitochondrial ultrastructure and function was present in the two hyperglycemic groups, most pronounced with concomitant HI. Affected mitochondrial respiratory chain enzyme activities were reduced to 25% to 62% of values in healthy rabbits, In the presence of up to five-fold increased tissue levels of glucose. This was accompanied by elevated levels of dicarbonyls, which may mediate direct toxicity of cellular glucose overload and accelerated glycolysis. The abnormalities were also present in myocardium, although to a lesser extent and absent in skeletal muscle.

Conclusions. In a rabbit model of critical illness, HG evokes cellular glucose overload in liver and myocardium inducing mitochondrial dysfunction, which explained the HG-induced organ damage. Maintenance of normoglycemia, but not HI, protects against such mitochondrial and organ damage. (Crit Care Med 2009; 37:1355-1364)

Item Type:	Journal Article
Subjects:	R Medicine > RC Internal medicine
Divisions:	Faculty of Medicine > Warwick Medical School > Translational & Systems Medicine > Metabolic and Vascular Health Faculty of Medicine > Warwick Medical School
Journal or Publication Title:	Critical Care Medicine
Publisher:	Lippincott Williams & Wilkins
ISSN:	0090-3493
Official Date:	April 2009
Volume:	Vol.37
Number:	No.4
Number of Pages:	10
Page Range:	pp. 1355-1364
Identification Number:	10.1097/CCM.0b013e31819cec17
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Supported by the Fund for Scientific Research (FWO), Flanders, Belgium, Research Council of the Katholieke Universiteit Leuven, Innovative Medizinische Forschung, Fund for Scientific Research (FWO), Flanders, Belgium, British Heart Foundation
Grant number:	G.0533.06, G0A2007/14, EL 610304
URI:	http://wrap.warwick.ac.uk/id/eprint/28221

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