Peroxisome proliferator-activated receptor gamma activation restores islet function in diabetic mice through reduction of endoplasmic reticulum stress and maintenance of euchromatin structure.
The nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-gamma) 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-gamma in the islet, we treated diabetic or glucose-intolerant mice with the PPAR-gamma 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 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-gamma agonist may be secondary to improvements in endoplasmic reticulum stress. Consistent with this possibility, incubation of thapsigargin-treated INS-1 beta cells with the PPAR-gamma agonist resulted in the reduction of endoplasmic reticulum stress and restoration of Pdx1 protein levels and Set7/9 nuclear occupancy. We conclude that PPAR-gamma 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.
Evans-Molina
Carmella
C
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Robbins
Reiesha D
RD
Kono
Tatsuyoshi
T
Tersey
Sarah A
SA
Vestermark
George L
GL
Nunemaker
Craig S
CS
Garmey
James C
JC
Deering
Tye G
TG
Keller
Susanna R
SR
Maier
Bernhard
B
Mirmira
Raghavendra G
RG
D000818:Animals; D001786:Blood Glucose; D004721:Endoplasmic Reticulum / Q000473:pathology*; D022041:Euchromatin / Q000648:ultrastructure*; D051273:Glucose Transporter Type 2 / Q000235:genetics; D018398:Homeodomain Proteins / Q000032:analysis / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics; D007515:Islets of Langerhans / Q000502:physiology* / Q000503:physiopathology*; D051379:Mice; D016688:Mice, Inbred NOD; D047495:PPAR gamma / Q000378:metabolism / Q000502:physiology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics; D015534:Trans-Activators / Q000032:analysis / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
C506944:Atp2a1 protein, mouse; D001786:Blood Glucose; D022041:Euchromatin; D051273:Glucose Transporter Type 2; D018398:Homeodomain Proteins; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D047495:PPAR gamma; C495682:Slc2a2 protein, mouse; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases