Nuclear factor-κB decoy oligodeoxynucleotides ameliorate impaired glucose tolerance and insulin resistance in mice with cecal ligation and puncture-induced sepsis*

Abstract

Insulin-resistant hyperglycemia is commonly observed in septic patients and may actually lead to some of adverse outcomes. We examined the changes in insulin signaling and glucose uptake regulation in sepsis and the involvement of the nuclear factor-kappaB pathway. Controlled animal study. University research laboratory. One hundred fifty-four BALB/c mice (8-12 wks of age). The following four experimental groups were studied: sham-operated control, cecal ligation and puncture-induced sepsis, sepsis + nuclear factor-kappaB decoy oligodeoxynucleotide treatment, and sepsis + scrambled decoy oligodeoxynucleotide treatment. Septic mice were markedly hyperinsulinemic with apparently normal blood glucose levels in the fasted state, suggesting they are insulin-resistant. In fact, glucose clearance in response to insulin was markedly impaired in septic mice. They had impaired GLUT4 membrane translocation resulting from impaired insulin signaling as indicated by the decreased amount of insulin receptor substrate protein and the reduced activation of phosphatidylinositol 3-kinase and Akt. Interestingly, injection of nuclear factor-kappaB decoy oligodeoxynucleotide into the skeletal muscle dramatically improved all of the changes, including glucose clearance and insulin signaling. We also found that the Cbl-associated protein to TC10 pathway, another pathway regulating GLUT4 translocation, was up-regulated in septic mice in a nuclear factor-kappaB-dependent manner. This pathway may be one of the compensatory mechanisms to translocate GLUT4 because silencing of the individual components of the pathway with small interfering RNAs further reduced GLUT4 translocation in muscles of septic mice. In sepsis, skeletal muscle GLUT4 translocation is impaired as a result of the reduced phosphatidylinositol 3-kinase/Akt pathway associated with insulin receptor substrate down-regulation through nuclear factor-kappaB activation.