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.author | Maganti, Aarthi V. | |
dc.contributor.author | Tersey, Sarah A. | |
dc.contributor.author | Syed, Farooq | |
dc.contributor.author | Nelson, Jennifer B. | |
dc.contributor.author | Colvin, Stephanie C. | |
dc.contributor.author | Maier, Bernhard | |
dc.contributor.author | Mirmira, Raghavendra G. | |
dc.contributor.department | Biochemistry and Molecular Biology, School of Medicine | en_US |
dc.date.accessioned | 2018-03-15T15:57:02Z | |
dc.date.available | 2018-03-15T15:57:02Z | |
dc.date.issued | 2016-10-21 | |
dc.description.abstract | Type 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.version | Final published version | en_US |
dc.identifier.citation | Maganti, 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.M116.741694 | en_US |
dc.identifier.issn | 0021-9258 | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/15580 | |
dc.language.iso | en_US | en_US |
dc.publisher | American Society for Biochemistry and Molecular Biology | en_US |
dc.relation.isversionof | 10.1074/jbc.M116.741694 | en_US |
dc.relation.journal | The Journal of Biological Chemistry | en_US |
dc.rights | Publisher Policy | en_US |
dc.source | PMC | en_US |
dc.subject | autoimmunity | en_US |
dc.subject | beta cell (B-cell) | en_US |
dc.subject | diabetes | en_US |
dc.subject | endoplasmic reticulum stress (ER stress) | en_US |
dc.subject | insulin | en_US |
dc.subject | peroxisome proliferator-activated receptor (PPAR) | en_US |
dc.subject | unfolded protein response (UPR) | en_US |
dc.title | 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 | en_US |
dc.type | Article | en_US |
ul.alternative.fulltext | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5077190/ | en_US |