Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
J Clin Invest. 2019 Aug 5;129(9):3717-3731. doi: 10.1172/JCI122445.
Palmitic acid esters of hydroxy stearic acids (PAHSAs) are endogenous antidiabetic and antiinflammatory lipids. Here, we show that PAHSAs protect against type 1 diabetes (T1D) and promote β cell survival and function. Daily oral PAHSA administration to nonobese diabetic (NOD) mice delayed the onset of T1D and markedly reduced the incidence of T1D, whether PAHSAs were started before or after insulitis was established. PAHSAs reduced T and B cell infiltration and CD4+ and CD8+ T cell activation, while increasing Treg activation in pancreata of NOD mice. PAHSAs promoted β cell proliferation in both NOD mice and MIN6 cells and increased the number of β cells in NOD mice. PAHSAs attenuated cytokine-induced apoptotic and necrotic β cell death and increased β cell viability. The mechanism appears to involve a reduction of ER stress and MAPK signaling, since PAHSAs lowered ER stress in NOD mice, suppressed thapsigargin-induced PARP cleavage in human islets, and attenuated ERK1/2 and JNK1/2 activation in MIN6 cells. This appeared to be mediated in part by glucagon-like peptide 1 receptor (GLP-1R) and not the G protein-coupled receptor GPR40. PAHSAs also prevented impairment of glucose-stimulated insulin secretion and improved glucose tolerance in NOD mice. Thus, PAHSAs delayed the onset of T1D and reduced its incidence by attenuating immune responses and exerting direct protective effects on β cell survival and function.
羟基硬脂酸的棕榈酸酯 (PAHSAs) 是内源性的抗糖尿病和抗炎脂质。在这里，我们表明 PAHSAs 可预防 1 型糖尿病 (T1D) 并促进 β 细胞存活和功能。每天口服 PAHSA 给药给非肥胖型糖尿病 (NOD) 小鼠可延迟 T1D 的发作，并显著降低 T1D 的发生率，无论 PAHSAs 是在胰岛炎建立之前还是之后开始给药。PAHSAs 减少了 T 和 B 细胞浸润以及 CD4+和 CD8+T 细胞的活化，同时增加了 NOD 小鼠胰腺中的 Treg 活化。PAHSAs 促进了 NOD 小鼠和 MIN6 细胞中的 β 细胞增殖，并增加了 NOD 小鼠中的 β 细胞数量。PAHSAs 减轻了细胞因子诱导的 β 细胞凋亡和坏死，并增加了 β 细胞的活力。其机制似乎涉及内质网应激和 MAPK 信号的减少，因为 PAHSAs 降低了 NOD 小鼠中的内质网应激，抑制了人胰岛中的 thapsigargin 诱导的 PARP 裂解，并减弱了 MIN6 细胞中 ERK1/2 和 JNK1/2 的激活。这似乎部分是通过胰高血糖素样肽 1 受体 (GLP-1R) 介导的，而不是 G 蛋白偶联受体 GPR40。PAHSAs 还防止了 NOD 小鼠中葡萄糖刺激的胰岛素分泌受损，并改善了葡萄糖耐量。因此，PAHSAs 通过减轻免疫反应并对 β 细胞存活和功能发挥直接保护作用，延迟了 T1D 的发作并降低了其发生率。
