Tissue-specific glucose toxicity induces mitochondrial damage in a burn injury model of critical illness.
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.
Vanhorebeek
Ilse
I
Department of Intensive Care Medicine, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
Ellger
Björn
B
De Vos
Rita
R
Boussemaere
Magaly
M
Debaveye
Yves
Y
Perre
Sarah Vander
SV
Rabbani
Naila
N
Thornalley
Paul J
PJ
Van den Berghe
Greet
G
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
D001786:Blood Glucose; D005947:Glucose