361-OR: ER Stress Attenuation Is Involved in PAHSA-Induced Reduction of T1D in Nonobese Diabetic (NOD) Mice

Palmitic Acid esters of Hydroxy Stearic Acids (PAHSAs) are endogenous lipids with antidiabetic and anti-inflammatory effects. We found that PAHSAs protect against T1D by attenuating autoimmune responses and by direct effects on islets. We aimed to determine the mechanisms by which PAHSAs directly promote β-cell survival. Daily oral gavage of PAHSAs in NOD mice starting at 4 or 13 weeks of age delays T1D onset and reduces T1D incidence from 82-90% of mice with vehicle to 35-40% of mice receiving PAHSAs. PAHSA treatment reduces leukocyte infiltration into islets by 50% and reduces T cell activation. PAHSA-treated mice had greater β-cell area relative to total islet area (vehicle 60±7 vs. PAHSA 77±1). PAHSAs enhance β-cell proliferation in NOD mice 5 fold vs. vehicle. PAHSA-treated NOD mice pancreata have lower ER stress markers, CHOP and XBP-1 (vehicle 68±12 vs. PAHSA 42±3), and higher insulin (vehicle 12±2 vs. PAHSA 17±1) immunostaining intensities per β-cell area. PAHSAs attenuate thapsigargin-induced PARP cleavage by 55% in human islets, and JNK1/2 phosphorylation by 40% in MIN6 cells. Also, PAHSAs attenuate apoptotic and necrotic β-cell death under cytokine stress and increase β-cell viability by 34% and proliferation by 31% (p<0.002). Since GLP-1 receptor (GLP-1R) antagonism causes β-cell death and G-protein coupled receptor GPR40 plays a vital role in β-cell function, we assessed if PAHSA beneficial effects on β-cell survival involve these pathways. In vitro, GLP-1R antagonism lowered PAHSA protective effects on β-cell viability by 53% and proliferation by 44% (p<0.005) under cytokine stress but GPR40 antagonism had no effect.

Conclusion: In addition to attenuating immune responses, PAHSAs delay the onset and reduce T1D incidence in NOD mice through direct effects. PAHSAs directly reduce cytokine-induced β-cell death and increase cell proliferation in autoimmune diabetes through mechanisms involving ER stress reduction. This appears to be mediated in part by GLP-1R and not by GPR40.