Peroxisome Proliferator-activated Receptor-γ Activation Augments the β-Cell Unfolded Protein Response and Rescues Early Glycemic Deterioration and β 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 β cells with subsequent endoplasmic reticulum stress and cellular death. Thiazolidinediones are insulin sensitizers that activate the nuclear receptor PPAR-γ and have been shown to partially ameliorate autoimmune type 1 diabetes in humans and non-obese diabetic (NOD) mice. We hypothesized that thiazolidinediones reduce β 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 β 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 β cell death, and increased β 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 β cells, as islets from mice treated with pioglitazone showed reductions in PPAR-γ (Ser-273) phosphorylation. Our results demonstrate that PPAR-γ activation directly improves β cell function and survival in NOD mice by enhancing the unfolded protein response and suggest that blockade of PPAR-γ (Ser-273) phosphorylation may prevent type 1 diabetes.
From the Department of Cellular and Integrative Physiology.|Center for Diabetes and Metabolic Diseases.
Aarthi V
AV
Maganti
Center for Diabetes and Metabolic Diseases.|Department of Pediatrics and the Herman B Wells Center.
Sarah A
SA
Tersey
Department of Pediatrics and the Herman B Wells Center.
Farooq
F
Syed
Department of Pediatrics and the Herman B Wells Center.
Jennifer B
JB
Nelson
Center for Diabetes and Metabolic Diseases.|Department of Pediatrics and the Herman B Wells Center.
Stephanie C
SC
Colvin
Center for Diabetes and Metabolic Diseases.|Department of Pediatrics and the Herman B Wells Center.
Bernhard
B
Maier
From the Department of Cellular and Integrative Physiology, rmirmira@iu.edu rmirmira@indianabiosciences.org.|Center for Diabetes and Metabolic Diseases.|Department of Pediatrics and the Herman B Wells Center.|Department of Medicine, and.|Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202 and.|Indiana Biosciences Research Institute, Indianapolis, Indiana 46202.
Raghavendra G
RG
Mirmira
D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D056811:Unfolded Protein Response / Q000187:drug effects*; D000071717:X-Box Binding Protein 1 / Q000235:genetics / Q000378:metabolism
C081452:Atf4 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D007328:Insulin; D047495:PPAR gamma; D045162:Thiazolidinediones; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D051701:Activating Transcription Factor 4; D000077205:Pioglitazone
autoimmunity; beta cell (B-cell); diabetes; endoplasmic reticulum stress (ER stress); insulin; peroxisome proliferator-activated receptor (PPAR); unfolded protein response (UPR)