Timing of insulin therapy affects the inflammatory response in endotoxemic rats

The aim of the present study was to determine whether timing of insulin administration influences the hepatic and serum proinflammatory and anti-inflammatory cytokines during endotoxemia stimulated by lipopolysaccharide (LPS). Eighty-one male Sprague-Dawley rats were divided into different time groups and insulin was given 30 min pre-LPS administration or hour 0, 1, 3, 6, 12, 24 after the induction of endotoxemia, respectively. Hepatic and serum proinflammatory cytokines IL-1β, IL-6, and TNF-α, and anti-inflammatory cytokine IL-10 were detected 24 and 48 h after the induction of endotoxemia. Compared with sham control rats, serum concentrations of proinflammatory cytokines IL-1β, IL-6, and TNF-α and anti-inflammatory cytokine IL-10 significantly increased on 24 and 48 h after induction of endotoxemia. Similarly, LPS administration also significantly increased the hepatic IL-1β, TNF-α, IL-6, and IL-10 protein concentration 48 h after LPS injection. Compared with levels in positive LPS controls animals receiving saline, on 24 and 48 h after LPS injection, insulin administrated ahead of 6 h after LPS injection significantly decreased the serum IL-1β, IL-6, and TNF-a concentration (P < 0.05), and significantly increased anti-inflammatory cytokine IL-10 concentration (P < 0.05); hepatic IL-1β and IL-6 expression were (P < 0.05) significantly decreased compared with levels in positive LPS controls. But, the significant decrease of hepatic TNF-a expression and significant increase of hepatic IL-10 were only seen in the animals in which insulin was administrated at 30 min pre-LPS or coadministrated with LPS. Insulin administrated 6 h after LPS injection lost the ability to significantly reduce serum or hepatic IL-1β, TNF-α, and IL-6 concentrations. Insulin has a protective role in systemic inflammatory response syndrome related to sepsis, such as downregulation of proinflammatory cytokines and upregulation of anti-inflammatory cytokine production. However, timing of insulin administrated may change its effect of inflammatory response in endotoxemic rats. Insulin administrated 6 h after LPS injection weaken the ability to protect inflammatory response related to sepsis.