title: Tissue-specific glucose toxicity induces mitochondrial damage in a burn injury model of critical illness.
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.
  
  
  METHODS
  Prospective, randomized laboratory investigation.
  
  
  METHODS
  University laboratory.
  
  
  METHODS
  Three-month-old male rabbits.
  
  
  METHODS
  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.
  
  
  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.
authors.affiliation: Department of Intensive Care Medicine, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
authors.forename: Ilse
authors.initials: I
authors.lastname: Vanhorebeek
authors.forename: Björn
authors.initials: B
authors.lastname: Ellger
authors.forename: Rita
authors.initials: R
authors.lastname: De Vos
authors.forename: Magaly
authors.initials: M
authors.lastname: Boussemaere
authors.forename: Yves
authors.initials: Y
authors.lastname: Debaveye
authors.forename: Sarah Vander
authors.initials: SV
authors.lastname: Perre
authors.forename: Naila
authors.initials: N
authors.lastname: Rabbani
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Thornalley
authors.forename: Greet
authors.initials: G
authors.lastname: Van den Berghe
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002056:Burns / Q000097:blood / Q000150:complications / Q000378:metabolism*; D016638:Critical Illness; D004195:Disease Models, Animal; D005947:Glucose / Q000633:toxicity; D006943:Hyperglycemia / Q000209:etiology; D006946:Hyperinsulinism / Q000209:etiology; D008297:Male; D008928:Mitochondria; D011817:Rabbits
chemical_list: D001786:Blood Glucose; D005947:Glucose