Alterations in β-Cell Sphingolipid Profile Associated with ER Stress and iPLA2β: Another Contributor to β-Cell Apoptosis in Type 1 Diabetes

Type 1 diabetes (T1D) development, in part, is due to ER stress-induced beta-cell apoptosis. Activation of the Ca2+-independent phospholipase A(2) beta (iPLA(2)beta) leads to the generation of pro-inflammatory eicosanoids, which contribute to beta-cell death and T1D. ER stress induces iPLA(2)beta-mediated generation of pro-apoptotic ceramides via neutral sphingomyelinase (NSMase). To gain a better understanding of the impact of iPLA(2)beta on sphingolipids (SLs), we characterized their profile in beta-cells undergoing ER stress. ESI/MS/MS analyses followed by ANOVA/Student's t-test were used to assess differences in sphingolipids molecular species in Vector (V) control and iPLA(2)beta-overexpressing (OE) INS-1 and Akita (AK, spontaneous model of ER stress) and WT-littermate (AK-WT) beta-cells. As expected, iPLA(2)beta induction was greater in the OE and AK cells in comparison with V and WT cells. We report here that ER stress led to elevations in pro-apoptotic and decreases in pro-survival sphingolipids and that the inactivation of iPLA(2)beta restores the sphingolipid species toward those that promote cell survival. In view of our recent finding that the SL profile in macrophages-the initiators of autoimmune responses leading to T1D-is not significantly altered during T1D development, we posit that the iPLA(2)beta-mediated shift in the beta-cell sphingolipid profile is an important contributor to beta-cell death associated with T1D.

Automated summary

The development of Type 1 diabetes is partly due to ER stress-induced beta-cell apoptosis, where iPLA(2)beta plays a significant role in the generation of pro-apoptotic ceramides. The study suggests that the shift in the beta-cell sphingolipid profile mediated by iPLA(2)beta could contribute to beta-cell death associated with T1D.