期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 129, 期 9, 页码 3717-3731出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI122445
关键词
-
资金
- NINDS P30 Core Center Grant [NS072030]
- NIH [R01 DK43051, P30 DK57521, R01 DK106210, K01 DK118041]
- Deutsche Forschungsgemeinschaft (DFG) Fellowship (MFRDC)
- JPB Foundation
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 beta 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 beta cell proliferation in both NOD mice and MINE cells and increased the number of beta cells in NOD mice. PAHSAs attenuated cytokine-induced apoptotic and necrotic beta cell death and increased beta 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 MINE 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 beta cell survival and function.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据