Type 1 diabetes (T1D) is a consequence of autoimmune destruction of β-cells and we find that the Ca2+-independent phospholipase A2β (iPLA2β) is induced in β-cells and immune cells and mitigation of iPLA2β attenuates β-cell death and T1D incidence. Activation of iPLA2β leads to generation of pro-inflammatory or anti-inflammatory bioactive lipids and we previously reported that iPLA2β activation favors M1 pro-inflammatory macrophage phenotype. Here, we utilized UPLC ESI-MS/MS protocols to assess the lipid profile generated by macrophages as a means to identify select lipids that are associated with T1D development. Macrophages were treated with DMSO (vehicle), IFNγ+LPS (to induce M1 polarization), or IL-4 (to induce M2 polarization) and at 16h, the media was collected and processed for assessment of eicosanoid class of bioactive lipids. Comparison of spontaneous diabetes-resistant C57BL/6J and spontaneous diabetes-prone NOD mice revealed that nearly all pro-inflammatory eicosanoids were elevated in NOD during the prediabetic phase, relative to C57. Theabundances increased in the NOD between 4-8 and decreased by 15 weeks, correlating with onset of insulitis. These findings are consistent with a higher inflammatory status in the NOD vs. C57. To assess contribution of iPLA2β to the lipid profile, macrophage responses in NOD were compared with those in NOD.iPLA2β-/+. Such analyses revealed that production of select pro-inflammatory and anti-inflammatory lipids were decreased and increased, respectively, from macrophages and islets of NOD.iPLA2β-/+, relative to age-matched NOD-WT, and this correlated with reduced T1D incidence in the NOD.iPLA2β-/+. We further find that iPLA2β-derived lipids (iDLs) play a critical role in alternative splicing events that favor generation of pro-apoptotic variants of several factors (Bcl-x, capsase-9, and RAGE). These findings raise the possibility that iDLs are candidates for targeting to counter T1D development.


A. Nelson: None. M.A. Park: None. C. Chalfant: None. S. Ramanadham: None.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.