Aberrant islet unfolded protein response in type 2 diabetes
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 a...
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| Veröffentlicht in: | Scientific reports 2014-02, Vol.4 (1), p.4054 |
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| description | 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. |
| doi_str_mv | 10.1038/srep04054 |
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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.</description><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/srep04054</identifier><identifier>PMID: 24514745</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 14 ; 14/63 ; 631/80/304 ; 631/80/470/1463 ; Activating transcription factor 1 ; Activating Transcription Factor 6 - metabolism ; Adult ; Aged ; Animal models ; Animals ; Child ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus, Type 2 - metabolism ; Diabetes Mellitus, Type 2 - pathology ; Diet, High-Fat ; Disease Models, Animal ; DNA-Binding Proteins - metabolism ; Endoplasmic reticulum ; Eukaryotic Initiation Factor-2 - metabolism ; Female ; Humanities and Social Sciences ; Humans ; Hyperglycemia ; Initiation factor eIF-2α ; Insulin ; Insulin - blood ; Insulin-Secreting Cells - cytology ; Insulin-Secreting Cells - metabolism ; Islets of Langerhans ; Islets of Langerhans - metabolism ; Islets of Langerhans - pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; Middle Aged ; multidisciplinary ; Obesity - etiology ; Obesity - metabolism ; Pancreas ; Phosphorylation ; Protein folding ; Proteins ; Regulatory Factor X Transcription Factors ; Rodents ; Science ; Transcription Factors - metabolism ; Unfolded Protein Response ; Young Adult</subject><ispartof>Scientific reports, 2014-02, Vol.4 (1), p.4054</ispartof><rights>The Author(s) 2014</rights><rights>Copyright Nature Publishing Group Feb 2014</rights><rights>Copyright © 2014, Macmillan Publishers Limited. 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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.</description><subject>13</subject><subject>14</subject><subject>14/63</subject><subject>631/80/304</subject><subject>631/80/470/1463</subject><subject>Activating transcription factor 1</subject><subject>Activating Transcription Factor 6 - metabolism</subject><subject>Adult</subject><subject>Aged</subject><subject>Animal models</subject><subject>Animals</subject><subject>Child</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes Mellitus, Type 2 - metabolism</subject><subject>Diabetes Mellitus, Type 2 - pathology</subject><subject>Diet, High-Fat</subject><subject>Disease Models, Animal</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Endoplasmic reticulum</subject><subject>Eukaryotic Initiation Factor-2 - metabolism</subject><subject>Female</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Hyperglycemia</subject><subject>Initiation factor eIF-2α</subject><subject>Insulin</subject><subject>Insulin - 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metabolism</topic><topic>Adult</topic><topic>Aged</topic><topic>Animal models</topic><topic>Animals</topic><topic>Child</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes Mellitus, Type 2 - metabolism</topic><topic>Diabetes Mellitus, Type 2 - pathology</topic><topic>Diet, High-Fat</topic><topic>Disease Models, Animal</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Endoplasmic reticulum</topic><topic>Eukaryotic Initiation Factor-2 - metabolism</topic><topic>Female</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Hyperglycemia</topic><topic>Initiation factor eIF-2α</topic><topic>Insulin</topic><topic>Insulin - blood</topic><topic>Insulin-Secreting Cells - cytology</topic><topic>Insulin-Secreting Cells - metabolism</topic><topic>Islets of Langerhans</topic><topic>Islets of Langerhans - metabolism</topic><topic>Islets of Langerhans - pathology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Obese</topic><topic>Middle Aged</topic><topic>multidisciplinary</topic><topic>Obesity - 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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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>24514745</pmid><doi>10.1038/srep04054</doi><oa>free_for_read</oa></addata></record> |
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| subjects | 13 14 14/63 631/80/304 631/80/470/1463 Activating transcription factor 1 Activating Transcription Factor 6 - metabolism Adult Aged Animal models Animals Child Diabetes Diabetes mellitus Diabetes Mellitus, Type 2 - metabolism Diabetes Mellitus, Type 2 - pathology Diet, High-Fat Disease Models, Animal DNA-Binding Proteins - metabolism Endoplasmic reticulum Eukaryotic Initiation Factor-2 - metabolism Female Humanities and Social Sciences Humans Hyperglycemia Initiation factor eIF-2α Insulin Insulin - blood Insulin-Secreting Cells - cytology Insulin-Secreting Cells - metabolism Islets of Langerhans Islets of Langerhans - metabolism Islets of Langerhans - pathology Male Mice Mice, Inbred C57BL Mice, Obese Middle Aged multidisciplinary Obesity - etiology Obesity - metabolism Pancreas Phosphorylation Protein folding Proteins Regulatory Factor X Transcription Factors Rodents Science Transcription Factors - metabolism Unfolded Protein Response Young Adult |
| title | Aberrant islet unfolded protein response in type 2 diabetes |
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