Role of calcium-independent phospholipase A(2)ß in human pancreatic islet ß-cell apoptosis.

ABSTRACT

Death of ß-cells due to apoptosis is an important contributor to ß-cell dysfunction in both type 1 and type 2 diabetes mellitus. Previously, we described participation of the Group VIA Ca(2+)-independent phospholipase A(2) (iPLA(2)ß) in apoptosis of insulinoma cells due to ER stress. To examine whether islet ß-cells are similarly susceptible to ER stress and undergo iPLA(2)ß-mediated apoptosis, we assessed the ER stress response in human pancreatic islets. Here, we report that the iPLA(2)ß protein is expressed predominantly in the ß-cells of human islets and that thapsigargin-induced ER stress promotes ß-cell apoptosis, as reflected by increases in activated caspase-3 in the ß-cells. Furthermore, we demonstrate that ER stress is associated with increases in islet iPLA(2)ß message, protein, and activity, iPLA(2)ß-dependent induction of neutral sphingomyelinase and ceramide accumulation, and subsequent loss of mitochondrial membrane potential. We also observe that basal activated caspase-3 increases with age, raising the possibility that ß-cells in older human subjects have a greater susceptibility to undergo apoptotic cell death. These findings reveal for the first time expression of iPLA(2)ß protein in human islet ß-cells and that induction of iPLA(2)ß during ER stress contributes to human islet ß-cell apoptosis. We hypothesize that modulation of iPLA(2)ß activity might reduce ß-cell apoptosis and this would be beneficial in delaying or preventing ß-cell dysfunction associated with diabetes.