Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients.
BACKGROUND
Maintenance of normoglycaemia by use of insulin reduces morbidity and mortality of patients in surgical intensive care. Studies on mitochondrial function in critical illness or diabetes suggest that effects of intensive insulin therapy on mitochondrial integrity contribute to the clinical benefits.


METHODS
Enzyme activities of the respiratory-chain complexes and oxidative-stress-sensitive glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were measured by spectrophotometry in 36 snap-frozen samples of liver and skeletal muscle obtained after death from patients who had been randomly assigned intensive (normoglycaemia) or conventional (hyperglycaemia) insulin therapy and who were similar in terms of admission diagnoses and causes of death. Mitochondrial ultrastructure was examined by electron microscopy in a random subgroup (n=20).


RESULTS
In the liver, hypertrophic mitochondria with an increased number of abnormal and irregular cristae and reduced matrix electron density were observed in seven of nine conventionally treated patients. Only one of 11 patients given intensive insulin treatment had these morphological abnormalities (p=0.005). The effect on ultrastructure was associated with higher activities of respiratory-chain complex I (median 1.53 [IQR 1.14-3.01] vs 0.81 [0.54-1.43] U/g liver; p=0.008) and complex IV (1.69 [1.40-1.97] vs 1.16 [0.97-1.40] U/g; p=0.008) in the intensive group than in the conventional group. There was no detectable difference in GAPDH activity. In skeletal muscle, mitochondrial ultrastructure and function were not affected by intensive insulin therapy.


CONCLUSIONS
Strict glycaemic control with intensive insulin therapy prevented or reversed ultrastructural and functional abnormalities of hepatocyte mitochondria. The lack of effect on skeletal-muscle mitochondria suggests a direct effect of glucose toxicity and glucose control, rather than of insulin, as the likely explanation.


CONCLUSIONS
Maintenance or restoration of mitochondrial function and cellular energetics is another therapeutic target, in addition to optimisation of cardiac output, systemic oxygen delivery, and regional blood flow, that might improve outcome for critically ill patients. Our findings could help to explain the mechanism underlying the reduction in mortality found when normoglycaemia was maintained with insulin, and further support use of intensive insulin therapy in this setting.
Vanhorebeek
Ilse
I
Departments of Intensive Care Medicine, Catholic University of Leuven, B-3000 Leuven, Belgium.
De Vos
Rita
R
Mesotten
Dieter
D
Wouters
Pieter J
PJ
De Wolf-Peeters
Christiane
C
Van den Berghe
Greet
G
D018806:APACHE; D000368:Aged; D001786:Blood Glucose / Q000032:analysis*; D002950:Citrate (si)-Synthase / Q000378:metabolism; D003422:Critical Care; D016638:Critical Illness; D004579:Electron Transport; D005260:Female; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000627:therapeutic use*; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000648:ultrastructure*; D008931:Mitochondria, Muscle / Q000378:metabolism / Q000648:ultrastructure; D009124:Muscle Proteins / Q000378:metabolism; D018384:Oxidative Stress; D016032:Randomized Controlled Trials as Topic; D018805:Sepsis / Q000378:metabolism
D001786:Blood Glucose; D007328:Insulin; D009124:Muscle Proteins; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D002950:Citrate (si)-Synthase