Peroxisome Proliferator-activated Receptor-γ Activation Augments the β-Cell Unfolded Protein Response and Rescues Early Glycemic Deterioration and β Cell Death in Non-obese Diabetic Mice

dc.contributor.authorMaganti, Aarthi V.
dc.contributor.authorTersey, Sarah A.
dc.contributor.authorSyed, Farooq
dc.contributor.authorNelson, Jennifer B.
dc.contributor.authorColvin, Stephanie C.
dc.contributor.authorMaier, Bernhard
dc.contributor.authorMirmira, Raghavendra G.
dc.contributor.departmentBiochemistry and Molecular Biology, School of Medicineen_US
dc.date.accessioned2018-03-15T15:57:02Z
dc.date.available2018-03-15T15:57:02Z
dc.date.issued2016-10-21
dc.description.abstractType 1 diabetes is an autoimmune disorder that is characterized by a failure of the unfolded protein response in islet β cells with subsequent endoplasmic reticulum stress and cellular death. Thiazolidinediones are insulin sensitizers that activate the nuclear receptor PPAR-γ and have been shown to partially ameliorate autoimmune type 1 diabetes in humans and non-obese diabetic (NOD) mice. We hypothesized that thiazolidinediones reduce β cell stress and death independently of insulin sensitivity. To test this hypothesis, female NOD mice were administered pioglitazone during the pre-diabetic phase and assessed for insulin sensitivity and β cell function relative to controls. Pioglitazone-treated mice showed identical weight gain, body fat distribution, and insulin sensitivity compared with controls. However, treated mice showed significantly improved glucose tolerance with enhanced serum insulin levels, reduced β cell death, and increased β cell mass. The effect of pioglitazone was independent of actions on T cells, as pancreatic lymph node T cell populations were unaltered and T cell proliferation was unaffected by pioglitazone. Isolated islets of treated mice showed a more robust unfolded protein response, with increases in Bip and ATF4 and reductions in spliced Xbp1 mRNA. The effect of pioglitazone appears to be a direct action on β cells, as islets from mice treated with pioglitazone showed reductions in PPAR-γ (Ser-273) phosphorylation. Our results demonstrate that PPAR-γ activation directly improves β cell function and survival in NOD mice by enhancing the unfolded protein response and suggest that blockade of PPAR-γ (Ser-273) phosphorylation may prevent type 1 diabetes.en_US
dc.eprint.versionFinal published versionen_US
dc.identifier.citationMaganti, A. V., Tersey, S. A., Syed, F., Nelson, J. B., Colvin, S. C., Maier, B., & Mirmira, R. G. (2016). Peroxisome Proliferator-activated Receptor-γ Activation Augments the β-Cell Unfolded Protein Response and Rescues Early Glycemic Deterioration and β Cell Death in Non-obese Diabetic Mice. The Journal of Biological Chemistry, 291(43), 22524–22533. https://doi.org/10.1074/jbc.M116.741694en_US
dc.identifier.issn0021-9258en_US
dc.identifier.urihttps://hdl.handle.net/1805/15580
dc.language.isoen_USen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biologyen_US
dc.relation.isversionof10.1074/jbc.M116.741694en_US
dc.relation.journalThe Journal of Biological Chemistryen_US
dc.rightsPublisher Policyen_US
dc.sourcePMCen_US
dc.subjectautoimmunityen_US
dc.subjectbeta cell (B-cell)en_US
dc.subjectdiabetesen_US
dc.subjectendoplasmic reticulum stress (ER stress)en_US
dc.subjectinsulinen_US
dc.subjectperoxisome proliferator-activated receptor (PPAR)en_US
dc.subjectunfolded protein response (UPR)en_US
dc.titlePeroxisome Proliferator-activated Receptor-γ Activation Augments the β-Cell Unfolded Protein Response and Rescues Early Glycemic Deterioration and β Cell Death in Non-obese Diabetic Miceen_US
dc.typeArticleen_US
ul.alternative.fulltexthttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5077190/en_US
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