Glucagon-stimulated but not Isoproterenol-stimulated Glucose Formation Inhibition by Interleukin-6 in Primary Cultured Rat Hepatocytes

Abstract

During prolonged sepsis, impairment of glucose supply by the liver leads to hypoglycemia. Our aim was to investigate whether proinflammatory cytokine interleukin-6, a major mediator of the hepatic acute phase reaction, could contribute to this impairment by inhibiting hepatic glucose production stimulated by glucagon or isoproterenol in rat hepatocytes. Interleukin-6 inhibited the stimulation of glucose formation from glycogen by glucagon but not by isoproterenol in cultured rat hepatocytes. This was confirmed in the perfused rat liver. In cultured hepatocytes, the increase in cyclic adenosine-3',5'-monophosphate formation by glucagon was inhibited by interleukin-6, which was probably due to attenuation of glucagon binding to the glucagon receptor. The increase in cyclic adenosine-3',5'-monophosphate stimulated by isoproterenol was not affected by interleukin-6. However, the cytokine inhibited both expression of the key gluconeogenic control enzyme, phosphoenolpyruvate carboxykinase, stimulated by glucagon and isoproterenol. Thus, while increased glucose demand during the acute-phase reaction might initially be accomplished by catecholamine-mediated stimulation of glucose formation from glycogen, inhibition of gluconeogenesis by interleukin-6 may contribute to the impairment of glucose homeostasis during the prolonged acute phase reaction.

Inhibition of Glucagon-Signaling and Downstream Actions by Interleukin 1β and Tumor Necrosis Factor α in Cultured Primary Rat Hepatocytes

“…Because the forskolin-stimulated increase in cAMP was not inhibited by rhIL1 and rhTNF ( ᭹ ᭤ Fig. 2 ) the cytokines must have impaired glucagon signal transduction at the site of or upstream from cAMP formation, for example, by disturbance of glucagon receptor function as has been demonstrated for IL6 inhibiting glucagon induction of PCK1 gene expression [17] . The activation of the transcription factor CREB by cAMP confers basal and cAMP-stimulated expression to the PCK1 gene [18] .…”