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 T2D patients. 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 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.