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

Type 1 diabetes is an autoimmune disorder that is characterized by a failure of the unfolded protein response in islet cells with subsequent endoplasmic reticulum stress and cellular death. Thiazolidinediones are insulin sensitizers that activate the nuclear receptor PPAR- and have been shown to partially ameliorate autoimmune type 1 diabetes in humans and non-obese diabetic (NOD) mice. We hypothesized that thiazolidinediones reduce 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 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 cell death, and increased 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 cells, as islets from mice treated with pioglitazone showed reductions in PPAR- (Ser-273) phosphorylation. Our results demonstrate that PPAR- activation directly improves cell function and survival in NOD mice by enhancing the unfolded protein response and suggest that blockade of PPAR- (Ser-273) phosphorylation may prevent type 1 diabetes.