PAHSAs attenuate immune responses and promote β cell survival in autoimmune diabetic mice
Ismail Syed, … , Diane Mathis, Barbara B. Kahn
Ismail Syed, … , Diane Mathis, Barbara B. Kahn
Published August 5, 2019
Citation Information: J Clin Invest. 2019;129(9):3717-3731. https://doi.org/10.1172/JCI122445.
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Research Article Autoimmunity Immunology

PAHSAs attenuate immune responses and promote β cell survival in autoimmune diabetic mice

Abstract

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.

Authors

Ismail Syed, Maria F. Rubin de Celis, James F. Mohan, Pedro M. Moraes-Vieira, Archana Vijayakumar, Andrew T. Nelson, Dionicio Siegel, Alan Saghatelian, Diane Mathis, Barbara B. Kahn

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Figure 5

PAHSA treatment attenuates β cell death by inhibiting ER stress.

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PAHSA treatment attenuates β cell death by inhibiting ER stress. Female ...
Female NOD mice were treated with vehicle or 5- and 9-PAHSA for 7 weeks starting at 4 weeks of age, and XBP-1 (A) and CHOP (B) intensities were determined by immunohistochemical analyses (n = 4–5 mice/group). *P < 0.05 versus vehicle-treated mice. Scale bars: 100 μm. Data indicate the mean ± SEM. Differences between groups were assessed by 2-tailed Student’s t test. (C) Human islets from nondiabetic donors were treated with thapsigargin (2 μmol/L) for 6 hours in the presence of 5-PAHSA or 9-PAHSA (20 μM each). Western blot analysis was performed with the cell lysates to determine PARP cleavage (n = 3 wells/condition, and each treatment condition had 250 islets in triplicate). Bar graphs show the densitometric analysis of the ratio of cleaved PARP to uncleaved PARP for each condition. *P < 0.05 versus control DMSO; #P < 0.05 versus thapsigargin. ND, not determined. MIN6 cells were treated with thapsigargin (0.5 μM) for 6 hours (D) or physiological glucose (5.5 mM) or high glucose (25 mM) for 24 hours (E) in the presence of 5- and/or 9-PAHSA (20 μM each). All conditions contained DMSO. Western blot analysis was performed to determine phosphorylation of JNK1/2 and ERK1/2 (n = 3 wells/condition). Bar graphs show the densitometric analysis of the ratio of p-JNK1 or p-JNK2 to the corresponding total JNK1 or JNK2 (D) and p-ERK1 or p-ERK2 to the corresponding total ERK1 or ERK2 (E) for each condition. SAPK, stress-activated protein kinase. *P < 0.05 versus no thapsigargin (D) or versus 5.5 mM glucose (E); #P < 0.05 versus thapsigargin (D). Densitometric analyses of the Western blots are an average of 3 lanes per condition. Data in C–E indicate the mean ± SEM. Differences between groups were assessed by ANOVA with Newman-Keuls multiple comparisons test.