Beta-cell apoptosis contributes to loss of β-cells and decreases in β-cell function in both types 1 and 2diabetes mellitus. It is therefore important to understand the mechanisms underlying β -cell apoptosis if this process is to be prevented or delayed. Our hypothesis is that the group VIA Ca2+-independent phospholipase A2 (iPLA2 β) participates in β -cell apoptosis. We observed that (a) ER stress, proinflammatory cytokines, and prolonged hyperglycemia promote expression and activity of iPLA2 β  inislets, (b) iPLA2 β  activation increases ceramide generation via neutral sphingomyelinase (NSMase)- catalyzed hydrolysis of sphingomyelins triggering the mitochondrial apoptotic pathway and β –cell apoptosis, (c) these outcomes are suppressed by inhibition of iPLA2 β  or NSMase, (d) iPLA2 β –null islets are less and iPLA2 β -transgenic (Tg) islets more sensitive to ER stress, (e) NSMase expression is unaffected in iPLA2 β -null islets and amplified in iPLA2 β -Tg islets, and (f) β -cell iPLA2 β  and NSMase messages are higher in the Akita mouse model of spontaneous β -cell ER stress that leads to diabetes. We also find that iPLA2 β  participates in human islet β -cell apoptosis induced by hyperglycemia and cytokines and that islet iPLA2 β  and NSMase messages are elevated in prediabetic NOD mice. Further, we recently found evidence for inhibition of iPLA2 β  leading to decreased incidence of T1D in diabetes-prone NOD mice. These findings strengthen our hypothesis thatiPLA2 β  participates in the onset and progression of T1D. We propose to validate our hypothesis in human T1D by correlating expression levels of iPLA2 β  with indices of beta-cell apoptosis in pancreas samples obtained from control and diabetic donor subjects.