Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients.

MITOCHONDRIA; ELECTRON microscopy; HYPOGLYCEMIC agents; INSULIN; GLUCOSE; HORMONES; THERAPEUTICS; CLINICAL medicine

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). Findings 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. Interpretation 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 ... [ABSTRACT FROM AUTHOR]

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