Death of β-cells due to apoptosis is an important contributor to β-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)β) in apoptosis of
insulinoma cells due to ER stress. To examine whether islet β-cells are similarly susceptible to ER stress and undergo iPLA(2)β-mediated apoptosis, we assessed the ER stress response in human pancreatic islets. Here, we report that the
iPLA(2)β
protein is expressed predominantly in the β-cells of human islets and that
thapsigargin-induced ER stress promotes β-cell apoptosis, as reflected by increases in activated
caspase-3 in the β-cells. Furthermore, we demonstrate that ER stress is associated with increases in islet
iPLA(2)β message,
protein, and activity, iPLA(2)β-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 β-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)β
protein in human islet β-cells and that induction of
iPLA(2)β during ER stress contributes to human islet β-cell apoptosis. We hypothesize that modulation of
iPLA(2)β activity might reduce β-cell apoptosis and this would be beneficial in delaying or preventing β-cell dysfunction associated with diabetes.