Investigation of the role of trail molecule on pancreatic beta cell proliferation

Therapeutic approaches to increase functional beta cell mass in diabetic patients are of great interest since loss of pancreatic beta cell mass and function contribute to development of both type-1 and type-2 diabetes. TRAIL (TNF-Related Apoptosis-Inducing Ligand), which is an apoptosis inducer in a wide variety of tumor cells, has also proven to promote survival and proliferation in various cell types, such as vascular smooth muscle cells and vascular endothelial cells. Furthermore, TRAIL is claimed to protect pancreatic beta cells against cytokine-related harm. We aimed to describe the biological effect of TRAIL on pancreatic beta cells and to investigate whether TRAIL could induce proliferation in these cells. Rat pancreatic islets and mouse insulinoma cell line (Min6) were used. Pancreatic islets were isolated from Wistar rats and enzymatically dispersed into single cells, then cultured. Cultures of dispersed rat islets contained mostly of beta cells, and remaining were alpha cells, fibroblast cells, and the other cell types. Cultures treated with increasing doses of recombinant sTRAIL (0, 1, 10 ng/ml) displayed no reduction in viable cell numbers. On the contrary, sTRAIL treatment induced proliferation of primary pancreatic beta cells compared to the untreated group. sTRAIL treatment also induced proliferation in Min6 beta cell line, while inducing apoptosis in A549 lung cancer cell line which was used as a control cell type. TRAIL expression was also increased in the pancreatic beta cell line and in A549 cells, by adenoviral gene delivery. Increased expression of TRAIL induced proliferation in Min6, while inducing apoptosis in A459 cells. Western Blot results suggest that TRAIL may promote beta cell proliferation through ERK1/2, p38 and Akt pathways. These results demonstrate that TRAIL does not induce apoptosis in primary rat beta cells or mouse beta cell line Min6, while increasing viability and proliferation. In conclusion, we believe that our results will contribute to the understanding of the biological role of TRAIL on beta cells, and suggest that TRAIL may be a candidate molecule to prevent beta cell loss and/or replenish beta cell mass, through further investigations.