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Protection of mitochondria by intensive insulin therapy in critical illness: blood glucose control or insulin?

Strict blood glucose control with intensive insulin therapy reduces the mortality and morbidity of critically ill patients [1]. To elucidate the relative impact of maintaining normoglycemia and glycemia-independent actions of insulin, we independently manipulated blood glucose (normal NG, high HG) and insulin levels (normal NI, high HI) in a rabbit model of prolonged critical illness [2]. We here focus on the mitochondrial compartment, which in the liver was shown to be protected by intensive insulin therapy [3].

In the liver, activities of all respiratory chain complexes are statistically similar for control and NI/NG rabbits. HI/NG rabbits have lower complex I activity than control or NI/NG animals and lower complex V activity than controls. Complexes I, II and V are further reduced in the NI/HG group and are even more severely affected in the HI/HG rabbits, with residual activities of 46%, 44% and 25% of control values, respectively. Complex III is only affected in HI/HG rabbits (62% of controls), whereas complex IV levels are similar in all groups. Complexes I, II, III and V are lower in HG vs NG groups. HI may negatively affect mitochondrial function and as such does not contribute to the protective effect of intensive insulin therapy on this cellular compartment. Compromised hepatic mitochondrial enzyme activities correlate with the degree of liver damage evaluated by serum ALT levels. Mitochondrial enzyme activities in the left ventricle are statistically equal for control, NI/NG and HI/NG rabbits. Complex III and V activities are lower in NI/HG than in NI/NG rabbits. Mitochondria of HI/HG rabbits are the most affected also in the heart, with residual activities of 76%, 84%, 61% and 47% compared with the NI/HG group for complexes I, II, III and V, respectively. Electron microscopic analysis confirmed the presence of severely damaged mitochondria in cardiac myocytes of HI/HG rabbits and is ongoing for liver.

In conclusion, the beneficial effect of intensive insulin therapy on hepatocytic mitochondria [3] is explained by avoiding glucose toxicity. The deleterious effect on both liver and cardiac mitochondria in the HI/HG group may be particularly important in view of the controversy surrounding glucose-insulin-potassium infusion and highlights the need for simultaneous glucose control when applying this therapy.

References

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Vanhorebeek, I., Ellger, B., De Vos, R. et al. Protection of mitochondria by intensive insulin therapy in critical illness: blood glucose control or insulin?. Crit Care 10, P241 (2006). https://doi.org/10.1186/cc4588

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Keywords

  • Critical Illness
  • Blood Glucose Control
  • Versus Activity
  • Intensive Insulin Therapy
  • Respiratory Chain Complex