Identification of Small Molecules That Protect Pancreatic β Cells against Endoplasmic Reticulum Stress-Induced Cell Death

Endoplasmic reticulum (ER) stress plays an important role in the decline in pancreatic beta cell function and mass observed in type 2 diabetes. Here, we developed a novel beta cell-based high-throughput screening assay to identify small molecules that protect beta cells against ER stress-induced cell death. Mouse beta TC6 cells were treated with the ER stressor tunicamycin to induce ER stress, and cell death was measured as a reduction in cellular ATP. A collection of 17600 compounds was screened for molecules that promote beta cell survival. Of the approximately 80 positive hits, two selected compounds were able to increase the survival of human primary beta cells and rodent beta cell lines subjected to ER stressors including palmitate, a free fatty acid of pathological relevance to diabetes. These compounds also restored ER stress-impaired glucose-stimulated insulin secretion responses. We show that the compounds promote beta cell survival by reducing the expression of key genes of the unfolded protein response and apoptosis, thus alleviating ER stress. Identification of small molecules that prevent ER stress-induced beta cell dysfunction and death may provide a new modality for the treatment of diabetes.