A Phenotypic Screen Identifies Calcium Overload As A Key Mechanism Of Beta-Cell Glucolipotoxicity

Type 2 diabetes (T2D) is caused by loss of pancreatic beta-cell mass and failure of the remaining beta-cells to deliver sufficient insulin to meet demand. beta-Cell glucolipotoxicity (GLT), which refers to combined, deleterious effects of elevated glucose and fatty acid levels on beta-cell function and survival, contributes to T2D-associated beta-cell failure. Drugs and mechanisms that protect beta-cells from GLT stress could potentially improve metabolic control in patients with T2D. In a phenotypic screen seeking low-molecular-weight compounds that protected beta-cells from GLT, we identified compound A that selectively blocked GLT-induced apoptosis in rat insulinoma cells. Compound A and its optimized analogs also improved viability and function in primary rat and human islets under GLT. We discovered that compound A analogs decreased GLT-induced cytosolic calcium influx in islet cells, and all measured beta-cell-protective effects correlated with this activity. Further studies revealed that the active compound from this series largely reversed GLT-induced global transcriptional changes. Our results suggest that taming cytosolic calcium overload in pancreatic islets can improve beta-cell survival and function under GLT stress and thus could be an effective strategy for T2D treatment.