BCL-XL Overexpression Protects Pancreatic beta-Cells against Cytokine- and Palmitate-Induced Apoptosis

Diabetes is a chronic disease that affects glucose metabolism, either by autoimmune-driven beta-cell loss or by the progressive loss of beta-cell function, due to continued metabolic stresses. Although both alpha- and beta-cells are exposed to the same stressors, such as proinflammatory cytokines and saturated free fatty acids (e.g., palmitate), only alpha-cells survive. We previously reported that the abundant expression of BCL-XL, an anti-apoptotic member of the BCL-2 family of proteins, is part of the alpha-cell defense mechanism against palmitate-induced cell death. Here, we investigated whether BCL-XL overexpression could protect beta-cells against the apoptosis induced by proinflammatory and metabolic insults. For this purpose, BCL-XL was overexpressed in two beta-cell lines-namely, rat insulinoma-derived INS-1E and human insulin-producing EndoC-beta H1 cells-using adenoviral vectors. We observed that the BCL-XL overexpression in INS-1E cells was slightly reduced in intracellular Ca2+ responses and glucose-stimulated insulin secretion, whereas these effects were not observed in the human EndoC-beta H1 cells. In INS-1E cells, BCL-XL overexpression partially decreased cytokine- and palmitate-induced beta-cell apoptosis (around 40% protection). On the other hand, the overexpression of BCL-XL markedly protected EndoC-beta H1 cells against the apoptosis triggered by these insults (>80% protection). Analysis of the expression of endoplasmic reticulum (ER) stress markers suggests that resistance to the cytokine and palmitate conferred by BCL-XL overexpression might be, at least in part, due to the alleviation of ER stress. Altogether, our data indicate that BCL-XL plays a dual role in beta-cells, participating both in cellular processes related to beta-cell physiology and in fostering survival against pro-apoptotic insults.