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

The Journal of Clinical Investigation
Ismail SyedBarbara B Kahn

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 to...Continue Reading

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Citations

Oct 17, 2019·Nutrients·Diego Hernández-Saavedra, Kristin I Stanford
Aug 6, 2019·The Journal of Clinical Investigation·Abdel Rahim A HamadHamid Rabb
Mar 11, 2020·The Journal of Biological Chemistry·Meric Erikci ErtuncAlan Saghatelian
Nov 22, 2020·Diabetes·Veronica L LiJonathan Z Long
Jan 8, 2021·Biochimie·Melha BenlebnaChristine Feillet-Coudray
Dec 30, 2020·Proceedings of the National Academy of Sciences of the United States of America·Kristyna BrejchovaOndrej Kuda
Nov 11, 2020·International Journal of Molecular Sciences·Adriana R Schultz MoreiraLaura Elisa Buitrago-Molina
Apr 8, 2021·Cell Metabolism·Anna SantoroBarbara B Kahn
Apr 13, 2021·Endocrine Reviews·John T WalkerAlvin C Powers
Aug 29, 2021·Pharmacology & Therapeutics·Martin RiecanOndrej Kuda

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Methods Mentioned

BETA
pancreatectomy
ELISA
flow cytometry
FACS
PMA

Software Mentioned

GraphPad
ImageJ
GraphPad Prism
FlowJo
Cytomix

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