Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic β cells
Background: Pancreatic β cell dysfunction and death are central in the pathogenesis of most if not all forms of diabetes. Understanding the molecular mechanisms underlying β cell failure is important to develop β cell protective approaches. Scope of review: Here we review the role of endoplasmic ret...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-09-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877817302636 |
| _version_ | 1818589769122185216 |
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| author | Miriam Cnop Sanna Toivonen Mariana Igoillo-Esteve Paraskevi Salpea |
| author_facet | Miriam Cnop Sanna Toivonen Mariana Igoillo-Esteve Paraskevi Salpea |
| author_sort | Miriam Cnop |
| collection | DOAJ |
| description | Background: Pancreatic β cell dysfunction and death are central in the pathogenesis of most if not all forms of diabetes. Understanding the molecular mechanisms underlying β cell failure is important to develop β cell protective approaches.
Scope of review: Here we review the role of endoplasmic reticulum stress and dysregulated endoplasmic reticulum stress signaling in β cell failure in monogenic and polygenic forms of diabetes. There is substantial evidence for the presence of endoplasmic reticulum stress in β cells in type 1 and type 2 diabetes. Direct evidence for the importance of this stress response is provided by an increasing number of monogenic forms of diabetes. In particular, mutations in the PERK branch of the unfolded protein response provide insight into its importance for human β cell function and survival. The knowledge gained from different rodent models is reviewed. More disease- and patient-relevant models, using human induced pluripotent stem cells differentiated into β cells, will further advance our understanding of pathogenic mechanisms. Finally, we review the therapeutic modulation of endoplasmic reticulum stress and signaling in β cells.
Major conclusions: Pancreatic β cells are sensitive to excessive endoplasmic reticulum stress and dysregulated eIF2α phosphorylation, as indicated by transcriptome data, monogenic forms of diabetes and pharmacological studies. This should be taken into consideration when devising new therapeutic approaches for diabetes. |
| first_indexed | 2024-12-16T09:45:54Z |
| format | Article |
| id | doaj.art-ef266eb46a2a45f08e77a609597facd7 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-16T09:45:54Z |
| publishDate | 2017-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-ef266eb46a2a45f08e77a609597facd72022-12-21T22:36:11ZengElsevierMolecular Metabolism2212-87782017-09-01691024103910.1016/j.molmet.2017.06.001Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic β cellsMiriam Cnop0Sanna Toivonen1Mariana Igoillo-Esteve2Paraskevi Salpea3ULB Center for Diabetes Research, Faculty of Medicine, Université Libre de Bruxelles, Brussels, BelgiumULB Center for Diabetes Research, Faculty of Medicine, Université Libre de Bruxelles, Brussels, BelgiumULB Center for Diabetes Research, Faculty of Medicine, Université Libre de Bruxelles, Brussels, BelgiumULB Center for Diabetes Research, Faculty of Medicine, Université Libre de Bruxelles, Brussels, BelgiumBackground: Pancreatic β cell dysfunction and death are central in the pathogenesis of most if not all forms of diabetes. Understanding the molecular mechanisms underlying β cell failure is important to develop β cell protective approaches. Scope of review: Here we review the role of endoplasmic reticulum stress and dysregulated endoplasmic reticulum stress signaling in β cell failure in monogenic and polygenic forms of diabetes. There is substantial evidence for the presence of endoplasmic reticulum stress in β cells in type 1 and type 2 diabetes. Direct evidence for the importance of this stress response is provided by an increasing number of monogenic forms of diabetes. In particular, mutations in the PERK branch of the unfolded protein response provide insight into its importance for human β cell function and survival. The knowledge gained from different rodent models is reviewed. More disease- and patient-relevant models, using human induced pluripotent stem cells differentiated into β cells, will further advance our understanding of pathogenic mechanisms. Finally, we review the therapeutic modulation of endoplasmic reticulum stress and signaling in β cells. Major conclusions: Pancreatic β cells are sensitive to excessive endoplasmic reticulum stress and dysregulated eIF2α phosphorylation, as indicated by transcriptome data, monogenic forms of diabetes and pharmacological studies. This should be taken into consideration when devising new therapeutic approaches for diabetes.http://www.sciencedirect.com/science/article/pii/S2212877817302636DiabetesEndoplasmic reticulum stresseIF2αPancreatic β cellInsulinIslet |
| spellingShingle | Miriam Cnop Sanna Toivonen Mariana Igoillo-Esteve Paraskevi Salpea Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic β cells Molecular Metabolism Diabetes Endoplasmic reticulum stress eIF2α Pancreatic β cell Insulin Islet |
| title | Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic β cells |
| title_full | Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic β cells |
| title_fullStr | Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic β cells |
| title_full_unstemmed | Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic β cells |
| title_short | Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic β cells |
| title_sort | endoplasmic reticulum stress and eif2α phosphorylation the achilles heel of pancreatic β cells |
| topic | Diabetes Endoplasmic reticulum stress eIF2α Pancreatic β cell Insulin Islet |
| url | http://www.sciencedirect.com/science/article/pii/S2212877817302636 |
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