TY - JOUR T1 - Peroxisome Proliferator-Activated Receptor γ Activation Restores Islet Function in Diabetic Mice through Reduction of Endoplasmic Reticulum Stress and Maintenance of Euchromatin Structure JF - Molecular and Cellular Biology JO - Mol. Cell. Biol. SP - 2053 LP - 2067 DO - 10.1128/MCB.01179-08 VL - 29 IS - 8 AU - Evans-Molina, Carmella AU - Robbins, Reiesha D. AU - Kono, Tatsuyoshi AU - Tersey, Sarah A. AU - Vestermark, George L. AU - Nunemaker, Craig S. AU - Garmey, James C. AU - Deering, Tye G. AU - Keller, Susanna R. AU - Maier, Bernhard AU - Mirmira, Raghavendra G. Y1 - 2009/04/15 UR - http://mcb.asm.org/content/29/8/2053.abstract N2 - The nuclear receptor peroxisome proliferator-activated receptor γ (PPAR-γ) is an important target in diabetes therapy, but its direct role, if any, in the restoration of islet function has remained controversial. To identify potential molecular mechanisms of PPAR-γ in the islet, we treated diabetic or glucose-intolerant mice with the PPAR-γ agonist pioglitazone or with a control. Treated mice exhibited significantly improved glycemic control, corresponding to increased serum insulin and enhanced glucose-stimulated insulin release and Ca2+ responses from isolated islets in vitro. This improved islet function was at least partially attributed to significant upregulation of the islet genes Irs1, SERCA, Ins1/2, and Glut2 in treated animals. The restoration of the Ins1/2 and Glut2 genes corresponded to a two- to threefold increase in the euchromatin marker histone H3 dimethyl-Lys4 at their respective promoters and was coincident with increased nuclear occupancy of the islet methyltransferase Set7/9. Analysis of diabetic islets in vitro suggested that these effects resulting from the presence of the PPAR-γ agonist may be secondary to improvements in endoplasmic reticulum stress. Consistent with this possibility, incubation of thapsigargin-treated INS-1 β cells with the PPAR-γ agonist resulted in the reduction of endoplasmic reticulum stress and restoration of Pdx1 protein levels and Set7/9 nuclear occupancy. We conclude that PPAR-γ agonists exert a direct effect in diabetic islets to reduce endoplasmic reticulum stress and enhance Pdx1 levels, leading to favorable alterations of the islet gene chromatin architecture. ER -