Role of calcium-independent phospholipase A2β in human pancreatic islet β-cell apoptosis

Lei X, Zhang S, Bohrer A, Barbour SE, Ramanadham S. Role of calcium-independent phospholipase A(2)beta in human pancreatic islet beta-cell apoptosis. Am J Physiol Endocrinol Metab 303: E1386-E1395, 2012. First published October 16, 2012; doi:10.1152/ajpendo.00234.2012.-Death of beta-cells due to apoptosis is an important contributor to beta-cell dysfunction in both type 1 and type 2 diabetes mellitus. Previously, we described participation of the Group VIA Ca2+-independent phospholipase A(2) (iPLA(2)beta) in apoptosis of insulinoma cells due to ER stress. To examine whether islet beta-cells are similarly susceptible to ER stress and undergo iPLA(2)beta-mediated apoptosis, we assessed the ER stress response in human pancreatic islets. Here, we report that the iPLA(2)beta protein is expressed predominantly in the beta-cells of human islets and that thapsigargin-induced ER stress promotes beta-cell apoptosis, as reflected by increases in activated caspase-3 in the beta-cells. Furthermore, we demonstrate that ER stress is associated with increases in islet iPLA(2)beta message, protein, and activity, iPLA(2)beta-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 beta-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)beta protein in human islet beta-cells and that induction of iPLA(2)beta during ER stress contributes to human islet beta-cell apoptosis. We hypothesize that modulation of iPLA(2)beta activity might reduce beta-cell apoptosis and this would be beneficial in delaying or preventing beta-cell dysfunction associated with diabetes.