-cell apoptosis

Death of -cells due to apoptosis is an important contributor to -cell dysfunction in both type 1 and type 2 diabetes mellitus. Previously, we described participation of the Group VIA Ca2-independent phos-pholipase A2 (iPLA2) in apoptosis of insulinoma cells due to ER stress. To examine whether islet -cells are similarly susceptible to ER stress and undergo iPLA2-mediated apoptosis, we assessed the ER stress response in human pancreatic islets. Here, we report that the iPLA2 protein is expressed predominantly in the -cells of human islets and that thapsigargin-induced ER stress promotes -cell apo-ptosis, as reflected by increases in activated caspase-3 in the -cells. Furthermore, we demonstrate that ER stress is associated with in-creases in islet iPLA2 message, protein, and activity, iPLA2-dependent induction of neutral sphingomyelinase and ceramide accu-mulation, and subsequent loss of mitochondrial membrane potential. We also observe that basal activated caspase-3 increases with age