Effects of hyperglycemia and insulin therapy on high mobility group box 1 in endotoxin-induced acute lung injury in a rat model

Objective: Hyperglycemia and insulin resistance are commonly seen in septic patients and are associated with increased morbidity and mortality. High mobility group box 1 (HMGB1) protein has been shown to play a key role as a significant factor in sepsis pathogenesis. This study investigated the increase in lung damage because of hyperglycemia and HMGB1 increase in a lipopolysaccharide-induced septic rat model and the potential for insulin therapy to reduce this lung damage by decreasing the serum level of HMGB1. Design: Randomized, prospective animal study. Setting: University medical center research laboratory. Subjects. Male Wistar rats. Interventions: Septic hyperglycemia was induced by infusion of glucose immediately after administration of lipopolysaccharide in rats. Measurements and Main Results. Animals were monitored for blood glucose. Separate cohorts were killed at 12 and 24 hrs postlipopolysaccharide administration and analyzed for HMGB1 and lung damage. The effects of insulin treatment were also examined. Hyperglycemic septic animals had significantly higher blood glucose and enhanced lung damage. In addition, HMGB1 was increased in the serum of hyperglycemic rats. On the other hand, insulin treatment for hyperglycemia resulted in significantly lower blood glucose and decreased both the lung damage and the serum level of HMGB1. In an in vitro study, insulin treatment inhibited the activation of NF-kappaB. Conclusions: Hyperglycemia is associated with higher HMGB1 levels and lung damage in sepsis. Insulin therapy significantly reduced lung damage, suggesting that management of hyperglycemia with insulin might decrease HMGB1 levels in the serum and lung tissue. One of the mechanisms that could contribute to the inhibition of HMGB1 secretion might be related to the inhibition of NF-kappa B.