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 September 3, 2019; First 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 3

PAHSA treatment increases islet β cell proliferation under cytokine stress.

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PAHSA treatment increases islet β cell proliferation under cytokine stre...
Female NOD mice were treated with vehicle or 5- and 9-PAHSAs for 7 weeks starting at 4 weeks of age. None of the vehicle- or PAHSA-treated mice at this age were diabetic and all had glycemia levels below 150 mg/dL following ad libitum feeding. (A) Islet inflammation and architecture. Scale bars: 100 μm. (B) Percentage of β cell and α cell area per islet. (C) β Cell cross-sectional area, β cell volume, β cell numbers, and insulin intensity. (D) β Cell proliferation and liver proliferation were determined by Ki67 staining (n = 4–7/group). *P < 0.05 versus vehicle-treated mice. For B–D, data indicate the mean ± SEM. Differences between groups were assessed by 2-tailed Student’s t test. (E) MIN6 cells were treated with cytomix (5 ng/mL TNF-α plus 5 ng/mL IL-1β plus 10 ng/mL IFN-γ) in the presence of 5- or 9-PAHSA (20 μm each) for 48 hours, and β cell proliferation was measured by BrdU incorporation (n = 10, for 8 wells/condition). #P < 0.05 versus control with no PAHSAs; *P < 0.05 versus cytomix alone and control alone. (F) Cell tracer–tracked MIN6 cells were treated with either diluent or IL-1β (10 ng/mL) for 48 hours in the presence of 5- or 9-PAHSA (5 and 20 μM). The percentage of MIN6 cell proliferation versus control was measured by flow cytometry (n = 3 wells/condition). *P < 0.05 versus control alone and IL-1β alone. Studies in E and F were performed twice. (G) MIN6 cells were treated with cytomix (5 ng/mL TNF-α plus 5 ng/mL IL-1β plus 10 ng/mL IFN-γ) in the presence of 5- and 9-PAHSAs (20 μM each), exendin(9-39) (10 nM), and GW1100 (10 μM) for 24 hours, and MIN6 cell proliferation was measured by BrdU incorporation into cells (n = 8 for 12 wells/condition). #P < 0.05 versus control alone; *P < 0.05 versus cytomix alone, and control alone; †P < 0.05 versus cytomix with PAHSAs. Data indicate the mean ± SEM. Differences between groups were assessed by ANOVA with Bonferroni’s multiple comparisons test.