Peroxisome proliferator-activated receptor γ activation restores islet function in diabetic mice through reduction of endoplasmic reticulum stress and maintenance of euchromatin structure

Carmella Evans-Molina, Reiesha D. Robbins, Tatsuyoshi Kono, Sarah A. Tersey, George L. Vestermark, Craig S. Nunemaker, James C. Garmey, Tye G. Deering, Susanna R. Keller, Bernhard Maier, Raghavendra G. Mirmira

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Abstract

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 Ca 2+ 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 historic 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 thap-sigargin-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.

Original languageEnglish (US)
Pages (from-to)2053-2067
Number of pages15
JournalMolecular and cellular biology
Volume29
Issue number8
DOIs
StatePublished - Apr 1 2009

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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