Diabetes as a disease of endoplasmic reticulum stress

• Published in: Diabetes/metabolism research and reviews Vol. 26; no. 8; pp. 611 - 621
• Main Authors: Thomas, Sally E., Dalton, Lucy E., Daly, Marie-Louise, Malzer, Elke, Marciniak, Stefan J.
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.11.2010; Wiley
• Subjects: Activating Transcription Factor 6 - physiology; Animals; Biological and medical sciences; diabetes; Diabetes Mellitus - physiopathology; Diabetes Mellitus, Type 1 - physiopathology; Diabetes. Impaired glucose tolerance; DNA-Binding Proteins - physiology; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Endoplasmic Reticulum - physiology; Endoribonucleases - physiology; Epiphyses - abnormalities; Epiphyses - physiopathology; ER stress; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fundamental and applied biological sciences. Psychology; General aspects; Glycoproteins - physiology; Humans; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - physiology; Islets of Langerhans - physiology; Medical sciences; Mice; Osteochondrodysplasias - physiopathology; PERK; Protein-Serine-Threonine Kinases - physiology; Regulatory Factor X Transcription Factors; Stress, Physiological - physiology; Transcription Factors - physiology; Unfolded Protein Response; UPR; Vertebrates: endocrinology; Endocrinopathy; Disease; Diabetes mellitus; UPR; ER stress; PERK; Endoplasmic reticulum; diabetes; Endocrinology; Stress
• ISSN: 1520-7552; 1520-7560
• DOI: 10.1002/dmrr.1132

Endoplasmic reticulum (ER) stress is an integral part of life for all professional secretory cells, but it has been studied to greatest depth in the pancreatic β‐cell. This reflects both the crucial role played by ER stress in the pathogenesis of diabetes and also the exquisite vulnerability of these cells to ER dysfunction. The adaptive cellular response to ER stress, the unfolded protein response, comprises mechanisms to both regulate new protein translation and a transcriptional program to allow adaptation to the stress. The core of this response is a triad of stress‐sensing proteins: protein kinase R‐like endoplasmic reticulum kinase (PERK), inositol‐requiring enzyme 1 (IRE1) and activating transcription factor 6. All three regulate portions of the transcriptional unfolded protein response, while PERK also attenuates protein synthesis during ER stress and IRE1 interacts directly with the c‐Jun amino‐terminal kinase stress kinase pathway. In this review we shall discuss these processes in detail, with emphasis given to their impact on diabetes and how recent findings indicate that ER stress may be responsible for the loss of β‐cell mass in the disease. Copyright © 2010 John Wiley & Sons, Ltd.