Interleukin-6 Enhances Glucose-Stimulated Insulin Secretion From Pancreatic β-Cells Potential Involvement of the PLC-IP3-Dependent Pathway

OBJECTIVE-Interleukin-6 (IL-6) has a significant impact on glucose metabolism. However, the effects of IL-6 on insulin secretion from pancreatic beta-cells are controversial. Therefore, we analyzed IL-6 effects on pancreatic beta-cell functions both in vivo and in vitro. RESEARCH DESIGN AND METHODS-First, to examine the effects of IL-6 on in vivo insulin secretion, we expressed IL-6 in the livers of mice using the adenoviral gene transfer system. In addition, using both MIN-6 cells, a murine beta-cell line, and pancreatic islets isolated from mice, we analyzed the in vitro effects of IL-6 pretreatment on insulin secretion. Furthermore, using pharmacological inhibitors and small interfering RNAs, we studied the intracellular signaling pathway through which IL-6 may affect insulin secretion from MIN-6 cells. RESULTS-Hepatic IL-6 expression raised circulating IL-6 and improved glucose tolerance due to enhancement of glucose stimulated-insulin secretion (GSIS). In addition, in both isolated pancreatic islets and MIN-6 cells, 24-h pretreatment with IL-6 significantly enhanced GSIS. Furthermore, pretreatment of MIN-6 cells with phospholipase C (PLC) inhibitors with different mechanisms of action, U-73122 and neomycin, and knockdowns of the IL-6 receptor and PLC-beta(1), but not with a protein kinase A inhibitor, H-89, inhibited IL-6-induced enhancement of GSIS. An inositol triphosphate (IP3) receptor antagonist, Xestospondin C, also abrogated the GSIS enhancement induced by IL-6. CONCLUSIONS-The results obtained from both in vivo and in vitro experiments strongly suggest that IL-6 acts directly on pancreatic beta-cells and enhances GSIS. The PLC-IP3-dependent pathway is likely to be involved in IL-6-mediated enhancements of GSIS. Diabetes 60:537-547, 2011