title: Aberrant islet unfolded protein response in type 2 diabetes.
abstract: The endoplasmic reticulum adapts to fluctuations in demand and copes with stress through an adaptive signaling cascade called the unfolded protein response (UPR). Accumulating evidence indicates that the canonical UPR is critical to the survival and function of insulin-producing pancreatic β-cells, and alterations in the UPR may contribute to the pathogenesis of type 2 diabetes. However, the dynamic regulation of UPR molecules in the islets of animal models and humans with type 2 diabetes remains to be elucidated. Here, we analyzed the expression of activating factor 6 (ATF6α) and spliced X-box binding protein 1 (sXBP1), and phosphorylation of eukaryotic initiation factor 2 (eIF2α), to evaluate the three distinct branches of the UPR in the pancreatic islets of mice with diet- or genetic-induced obesity and insulin resistance. ATF6 and sXBP1 expression was predominantly found in the β-cells, where hyperglycemia coincided with a decline in expression in both experimental models and in humans with type 2 diabetes. These data suggest alterations in the expression of UPR mediators may contribute to the decline in islet function in type 2 diabetes in mice and humans.
authors: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115.
authors: Feyza
authors: F
authors: Engin
authors: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115.
authors: Truc
authors: T
authors: Nguyen
authors: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115.
authors: Alena
authors: A
authors: Yermalovich
authors: 1] Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115 [2] Broad Institute of Harvard and MIT, Harvard School of Public Health, Boston, MA 02115.
authors: Gökhan S
authors: GS
authors: Hotamisligil
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000328:Adult; D000368:Aged; D000818:Animals; D002648:Child; D004268:DNA-Binding Proteins / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008875:Middle Aged; D009765:Obesity / Q000209:etiology / Q000378:metabolism; D010766:Phosphorylation; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D056811:Unfolded Protein Response; D055815:Young Adult
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D004268:DNA-Binding Proteins; D015852:Eukaryotic Initiation Factor-2; D007328:Insulin; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors