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 1

Chronic PAHSA treatment delays the onset and reduces the incidence of diabetes in NOD mice.

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Chronic PAHSA treatment delays the onset and reduces the incidence of di...
Female NOD mice were treated with vehicle and 5- and 9-PAHSA (each 15 mg/kg BE/day). (A) Serum 5- and 9-PAHSA levels at 6 weeks of PAHSA treatment. n = 5–6/group. *P < 0.05 versus vehicle. Data indicate the mean ± SEM. Differences between groups were assessed by 2-tailed Student’s t test. (B) Body weight over 26 weeks of treatment, starting from 4 weeks of age. n = 22–23/group. (C) Cumulative diabetes incidence in NOD mice treated with PAHSAs for 26 weeks starting at 4 weeks of age (n = 22–23/group). **P < 0.001 versus vehicle. Differences between groups were assessed by log-rank test (z = 4.12). (D) Cumulative diabetes incidence in NOD mice treated with PAHSAs for 13 weeks starting at 13 weeks of age (n = 13/group). **P < 0.001 versus vehicle. Differences between groups were assessed by log-rank test (z = 3.51). (E) Serum insulin levels at 6 and 13 weeks of PAHSA treatment in ad libitum–fed NOD mice from the early intervention group (n = 14–12/group). *P < 0.05 versus vehicle. Data indicate the mean ± SEM. Differences between groups were assessed by 2-tailed Student’s t test. (F) Serum total GLP-1 levels at 15 weeks of PAHSA treatment (n = 12/group). The red data points represent diabetic mice in the vehicle- and PAHSA-treated groups. Glucose-stimulated insulin secretion (GSIS) (G) and glycemia during GSIS (H) at 9 weeks of PAHSA treatment (n = 10–11/group). *P < 0.05 versus the t0 time point within the group. (I) Oral glucose tolerance test (OGTT) at 11 weeks of PAHSA treatment. n = 9–11/group. *P < 0.05 versus vehicle. For G–I, data indicate the mean ± SEM. Differences between groups were assessed by a repeated-measures ANOVA with a Newman-Keuls multiple-comparisons test. For E–I, only nondiabetic mice were included in the study. For G, the only PAHSA-treated mouse that did not show an increase in insulin secretion in response to glucose at 13 weeks of age subsequently became diabetic at 17 weeks of age.