Strict blood glucose control with insulin improves hepatic mitochondrial ultrastructure and function in critical illness

Abstract

Hyperglycemia and insulin resistance are common in critical illness. Recently, a reduction of morbidity and mortality of patients in a surgical ICU by maintaining normoglycemia with insulin has been demonstrated [1]. Studies on mitochondria in sepsis [2] and other critical illness and on hyperglycemia in diabetes [3] suggested that the effects of this therapy on mitochondrial integrity and oxidative stress state may contribute to the positive results of the treatment. Twenty liver biopsies obtained postmortem from patients randomized to intensive insulin therapy (IIT) or conventional insulin therapy (CIT) were randomly selected for mitochondrial investigation. Studied patients in the CIT and IIT groups were comparable for age and type, severity and duration of critical illness. The mean blood glucose levels were 10.5 ± 0.6 and 5.6 ± 0.4 mmol/l (P < 0.0001) on a median daily insulin dose of 31 and 45 IU (P = 0.3), respectively. Hypertrophic mitochondria with an increased number of abnormal and irregular cristae and reduced electron-density of the matrix were observed by electron microscopy for seven of the nine patients in the CIT group, in contrast to only one of the 11 IIT patients (P = 0.0018). In addition, significantly higher activities of complex III and complex IV of the respiratory chain and a trend for higher activities of complex I, complex II and complex V and glyceraldehyde-3-P dehydrogenase, an enzyme of which the inhibition by superoxide has been linked to hyperglycemic complications in diabetes [3], were found in the IIT as compared with the CIT group. In conclusion, maintenance of normoglycemia with IIT appeared to prevent ultrastructural and functional abnormalities of hepatocytic mitochondria associated with critical illness-induced hyperglycemia. These alterations may have contributed to the benefits of the intervention. Further analyses are needed to link the positive effect of IIT on mitochondrial integrity to an effect on oxidative stress state in critical illness.