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Insulin signaling in critical illness: intensive versus conventional insulin therapy

Insulin resistance and hyperglycemia are common in critical illness. We recently demonstrated that strict maintenance of normoglycemia with intensive insulin therapy during intensive care reduced morbidity and mortality of surgical ICU patients [1]. Little is known, however, about insulin signaling in critical illness. There are two main insulin signaling pathways: the metabolic IRS-phosphatidylinositol-3-kinase (PI3K) pathway, which is impaired in type 2 diabetes, and the mitogenic MAPK pathway. The aim of the present study is to examine the effect of intensive insulin therapy on insulin signaling.

A random selection of 36 non-survivors, who had been randomized to intensive (normoglycemic) or conventional (hyperglycemic) insulin therapy, was comparable for age and severity, duration and type of critical illness. The mean blood glucose levels were 5.6 ± 0.4 and 9.9 ± 0.9 mmol/l (P < 0.001) on a median daily insulin dose of 44.2 and 14.4 IU (P = 0.005), respectively. Snap-frozen postmortem liver and skeletal muscle biopsies were homogenized and protein levels of signaling molecules were quantified with immunoprecipitation (IRS1 + PI3K and SHC + Grb2), western blotting (phosphorylated Akt) and ELISA (phosphorylated p42/44MAPK).

In the muscle and liver, intensive insulin therapy significantly stimulated the association of IRS with the p85 subunit of PI3K as compared with conventional therapy. The phosphorylation of the downstream signaling molecule Akt was increased in the muscle but not in the liver. To study the effect of intensive insulin therapy on the MAPK pathway, we measured the association of SHC with Grb2 and the phosphorylation of the downstream activator p42/44 MAPK. The two therapy groups did not differ in the amount of associated SHC-Grb2, in neither the muscle nor the liver. There was also no detectable difference in phosphorylated p42/44 MAPK levels.

In conclusion, metabolic insulin resistance in the critically ill, as revealed by an impaired PI3K pathway, can be overcome with intensive insulin therapy in skeletal muscle but not in the liver. Interestingly, liver insulin resistance is associated with an impaired activation of Akt, but not its upstream regulator PI3K. The MAPK pathway is not activated by intensive insulin therapy. Whether unresponsiveness of the mitogenic signal transduction is due to maximal stimulation of this pathway via other signals during critical illness is being explored.

References

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Langouche, L., Vander Perre, S., Wouters, P. et al. Insulin signaling in critical illness: intensive versus conventional insulin therapy. Crit Care 9, P384 (2005). https://doi.org/10.1186/cc3447

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Keywords

  • Insulin Therapy
  • Insulin Signaling
  • Critical Illness
  • MAPK Pathway
  • Intensive Insulin Therapy