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Perturbations in endoplasmic reticulum (ER) homeostasis can evoke stress responses leading to aberrant glucose and lipid metabolism. ER dysfunction is linked to inflammatory disorders, but its role in the pathogenesis of autoimmune type 1 diabetes (T1D) remains unknown. We identified defects in the expression of unfolded protein response (UPR) mediators ATF6 (activating transcription factor 6) and XBP1 (X-box binding protein 1) in β cells from two different T1D mouse models and then demonstrated similar defects in pancreatic β cells from T1D patients. Administration of a chemical ER stress mitigator, tauroursodeoxycholic acid (TUDCA), at the prediabetic stage resulted in a marked reduction of diabetes incidence in the T1D mouse models. This reduction was accompanied by (i) a significant decrease in aggressive lymphocytic infiltration in the pancreas, (ii) improved survival and morphology of β cells, (iii) reduced β cell apoptosis, (iv) preserved insulin secretion, and (v) restored expression of UPR mediators. TUDCA's actions were dependent on ATF6 and were lost in mice with β cell-specific deletion of ATF6. These data indicate that proper maintenance of the UPR is essential for the preservation of β cells and that defects in this process can be chemically restored for preventive or therapeutic interventions in T1D.
Pubmed ID: 24225943
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THIS RESOURCE IS NO LONGER IN SERVICE. Documented on October 27,2023. Core that provides cell sorting and flow cytometry services. Specific services include cell analysis, large object sorting,magnetic cell enrichment, and automatic cell counting.
View all literature mentionsTHIS RESOURCE IS NO LONGER IN SERVICE. Documented on October 27,2023. Core that provides services for performing specific morphological procedures, providing training and access to equipment, maintaining the specialized microscopes, and giving advice and interpretation.
View all literature mentionsTHIS RESOURCE IS NO LONGER IN SERVICE. Documented on October 27,2023. Core that provides technically advanced physiological evaluation of metabolism in diabetes, obesity, and their associated complications in rodents for DRC investigators and outside users. It also provides training of investigators and trainees in several physiological procedures.
View all literature mentionsTHIS RESOURCE IS NO LONGER IN SERVICE. Documented on October 27,2023. Core that provides services for genetic and genomic analysis, including DNA extraction from blood, access to DNA collections from the Core?s repository, SNP genotyping, and support for gene expression studies based on both high-density oligonucleotide arrays and real-time quantitative PCR.
View all literature mentionsCore that maintains a centralized facility for the generation and propagation of reprogrammed iPS cells for use in molecular and cellular pathologies underlying diabetes and its complications.
View all literature mentionsSix component core which facilitates the exchange of research information and discussions among investigators, fellows and students within the Joslin Diabetes Center, as well as between Joslin Staff and outside researchers with similar interests.
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The NIDDK Information Network (dkNET) serves the needs of basic and clinical investigators by providing seamless access to large pools of data and research resources relevant to the mission of The National Institute of Diabetes Digestive and Kidney Diseases (NIDDK). dkNET is hosted at University of California San Diego, and is supported by NIH NIDDK grant U24DK097771.
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