Maganti, Aarthi V.Tersey, Sarah A.Syed, FarooqNelson, Jennifer B.Colvin, Stephanie C.Maier, BernhardMirmira, Raghavendra G.2018-03-152018-03-152016-10-21Maganti, 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.M116.7416940021-9258https://hdl.handle.net/1805/15580Type 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-USPublisher Policyautoimmunitybeta cell (B-cell)diabetesendoplasmic reticulum stress (ER stress)insulinperoxisome proliferator-activated receptor (PPAR)unfolded protein response (UPR)Article