INTERLEUKIN-1-BETA AND INTERLEUKIN-6, BUT NOT TUMOR-NECROSIS-FACTOR-ALPHA, INHIBIT INSULIN-STIMULATED GLYCOGEN-SYNTHESIS IN RAT HEPATOCYTES

Recent evidence indicates that inflammatory cytokines are involved in changes of blood glucose concentrations and hepatic glucose metabolism in infectious diseases, including sepsis. However, little is known re garding how cytokines interact with glucoregulatory hormones such as i nsulin. The objective of the present study is to investigate if and ho w cytokines influence insulin-stimulated glycogen metabolism in the li ver. Interleukin 1 beta (IL-1 beta) and interleukin 6 (IL-6) markedly inhibited the increase of glycogen deposition stimulated by insulin in primary rat hepatocyte cultures; however, tumor necrosis factor or ha d no effect. Labeling experiments revealed that both cytokines counter acted insulin action by decreasing [C-14]-glucose incorporation into g lycogen and by increasing [C-14]-glycogen degradation. Furthermore, it was discovered that IL-1 beta and IL-6 inhibited glycogen synthase ac tivity and, in contrast, accelerated glycogen phosphorylase activity. In experiments with kinase inhibitors, serine/threonine kinase inhibit or K252a blocked IL-1 beta- and IL-6-induced inhibitions of glycogen d eposition, as well as glycogen synthase activity whereas another kinas e inhibitor staurosporine blocked only IL-6-induced inhibition. Tyrosi ne kinase inhibitor herbimycin A blocked only IL-1 beta-induced inhibi tion. These results indicate that IL-1 beta and IL-6 replate insulin-s timulated glycogen synthesis through different pathways involving prot ein phosphorylation in hepatocytes, They may mediate the change of hep atic glucose metabolism under pathological and even physiological cond itions by modifying insulin action in vivo.