Peroxisome Proliferator-Activated Receptor γ Activation Restores Islet Function in Diabetic Mice through Reduction of Endoplasmic Reticulum Stress and Maintenance of Euchromatin Structure

Abstract

The nuclear receptor peroxisome proliferator-activated receptor ␥ (PPAR-␥) 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-␥ in the islet, we treated diabetic or glucose-intolerant mice with the PPAR-␥ 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-␥ agonist may be secondary to improvements in endoplasmic reticulum stress. Consistent with this possibility, incubation of thapsigargin-treated INS-1 ␤ cells with the PPAR-␥ agonist resulted in the reduction of endoplasmic reticulum stress and restoration of Pdx1 protein levels and Set7/9 nuclear occupancy. We conclude that PPAR-␥ 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.Type 2 diabetes mellitus results from a combination of insulin resistance and progressive islet dysfunction (46). In many individuals, ␤-cell failure may precede the clinical diagnosis of diabetes, and landmark studies such as the United Kingdom Prospective Diabetes Study have shown a continued decrement in ␤-cell function despite treatment intervention with sulfonylureas, metformin, and insulin (52). Thiazolidinediones are orally active agents used in the treatment of type 2 diabetes that act as agonists for the nuclear transcription factor peroxisome proliferator-activated receptor ␥ (PPAR-␥) (60). Although thiazolidinediones are classically thought to act as peripheral insulin sensitizers, there is growing evidence from studies of human and animal models that these agents may also act to preserve and/or enhance ␤-cell function in the setting of progressive type 2 diabetes and insulin resistance (3, 12). PPAR-␥ is known to be expressed in the pancreatic islet (8, 48), and PPAR-responsive elements have been identified in the promoters of genes involved in glucose-stimulated insulin secretion, including Glut2, Gck, and Pdx1 (16,21,26,27,33). Reports from studies of ␤-cell lines, rodent models of progressive type 2 diabetes, and humans at risk for type 2 diabetes suggest that PPAR-␥ agonist administration leads to preservation of islet mass and function (10,13,18,22,25,33,57,58).Whereas the studies noted ab...

Peroxisome Proliferator-activated Receptor γ (PPARγ) and Its Target Genes Are Downstream Effectors of FoxO1 Protein in Islet β-Cells

“…As such, this mouse showed a phenotype of functional ␤-cell failure, with an expression profile that agreed exactly with the proposed signaling pathway in this study. Also, others have reported PPAR␥ regulation of gene expression for GLUT2 (53), glucokinase (54), and GPR40 (55) in ␤-cells, plus key modulatory effects of PPAR␥ in ␤-cell endoplasmic reticulum stress related to a cytokine-induced loss of SERCA2 expression have been shown (56,57). In addition, numerous ␤-cell effects have been attributed to PPAR␥ from thiazolidinedione studies in islets, insulin-containing cell lines, and various animal models, although direct proof that the findings are PPAR␥-mediated is mostly lacking.…”

Inhibition of Deoxyhypusine Synthase Enhances Islet β Cell Function and Survival in the Setting of Endoplasmic Reticulum Stress and Type 2 Diabetes

“…INS-1 (832/13) cells treated with 1 M thapsigargin (Tg) exhibit ER stress and defects in intracellular calcium homeostasis similar to those seen in islets from diabetic db/db mice (11,32). Tg is an inhibitor of the sarco-endoplasmic reticulum Ca 2ϩ ATPase, and causes the rapid activation of the unfolded protein response (UPR) as observed in ER stress.…”

“…Treatment was initiated at 8 -12 weeks of age and continued for 14 days. Intraperitoneal glucose tolerance tests (GTTs) using 0.1-1 mg/kg glucose and insulin tolerance tests using 3 units/kg insulin intraperitoneally were performed as described previously (11). Blood glucose concentrations were measured using a handheld glucometer (Abbott).…”

“…cytokines causing inflammation or hyperglycemia causing oxidative stress) can evoke the other pathways chronically. Thus, drugs that show efficacy in any of these pathways (such as PPAR␥ agonists (11) and antioxidants (12)) may serve to globally reduce ␤ cell stress in type 2 diabetes.…”

SET7/9 Enzyme Regulates Cytokine-induced Expression of Inducible Nitric-oxide Synthase through Methylation of Lysine 4 at Histone 3 in the Islet β Cell

“…1C), indicating that SET7/9 does not regulate NF-B protein stability in ␤ cells. SET7/9 has also been shown to shuttle between the nucleus and cytosol in response to various stimuli (33,34). To investigate the effect of cytokines on SET7/9 intracellular distribution, SET7/9 content was evaluated in total, nuclear, and cytosolic fractions isolated from ␤TC3 cells before and after cytokine treatment.…”