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β-Cell Dysfunction Due to Increased ER Stress in a Stem Cell Model of Wolfram Syndrome
Wolfram syndrome is an autosomal recessive disorder caused by mutations in WFS1 and is characterized by insulin-dependent diabetes mellitus, optic atrophy, and deafness. To investigate the cause of β-cell failure, we used induced pluripotent stem cells to create insulin-producing cells from individu...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931392/ https://www.ncbi.nlm.nih.gov/pubmed/24227685 http://dx.doi.org/10.2337/db13-0717 |
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author | Shang, Linshan Hua, Haiqing Foo, Kylie Martinez, Hector Watanabe, Kazuhisa Zimmer, Matthew Kahler, David J. Freeby, Matthew Chung, Wendy LeDuc, Charles Goland, Robin Leibel, Rudolph L. Egli, Dieter |
author_facet | Shang, Linshan Hua, Haiqing Foo, Kylie Martinez, Hector Watanabe, Kazuhisa Zimmer, Matthew Kahler, David J. Freeby, Matthew Chung, Wendy LeDuc, Charles Goland, Robin Leibel, Rudolph L. Egli, Dieter |
author_sort | Shang, Linshan |
collection | PubMed |
description | Wolfram syndrome is an autosomal recessive disorder caused by mutations in WFS1 and is characterized by insulin-dependent diabetes mellitus, optic atrophy, and deafness. To investigate the cause of β-cell failure, we used induced pluripotent stem cells to create insulin-producing cells from individuals with Wolfram syndrome. WFS1-deficient β-cells showed increased levels of endoplasmic reticulum (ER) stress molecules and decreased insulin content. Upon exposure to experimental ER stress, Wolfram β-cells showed impaired insulin processing and failed to increase insulin secretion in response to glucose and other secretagogues. Importantly, 4-phenyl butyric acid, a chemical protein folding and trafficking chaperone, restored normal insulin synthesis and the ability to upregulate insulin secretion. These studies show that ER stress plays a central role in β-cell failure in Wolfram syndrome and indicate that chemical chaperones might have therapeutic relevance under conditions of ER stress in Wolfram syndrome and other forms of diabetes. |
format | Online Article Text |
id | pubmed-3931392 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-39313922015-03-01 β-Cell Dysfunction Due to Increased ER Stress in a Stem Cell Model of Wolfram Syndrome Shang, Linshan Hua, Haiqing Foo, Kylie Martinez, Hector Watanabe, Kazuhisa Zimmer, Matthew Kahler, David J. Freeby, Matthew Chung, Wendy LeDuc, Charles Goland, Robin Leibel, Rudolph L. Egli, Dieter Diabetes Metabolism Wolfram syndrome is an autosomal recessive disorder caused by mutations in WFS1 and is characterized by insulin-dependent diabetes mellitus, optic atrophy, and deafness. To investigate the cause of β-cell failure, we used induced pluripotent stem cells to create insulin-producing cells from individuals with Wolfram syndrome. WFS1-deficient β-cells showed increased levels of endoplasmic reticulum (ER) stress molecules and decreased insulin content. Upon exposure to experimental ER stress, Wolfram β-cells showed impaired insulin processing and failed to increase insulin secretion in response to glucose and other secretagogues. Importantly, 4-phenyl butyric acid, a chemical protein folding and trafficking chaperone, restored normal insulin synthesis and the ability to upregulate insulin secretion. These studies show that ER stress plays a central role in β-cell failure in Wolfram syndrome and indicate that chemical chaperones might have therapeutic relevance under conditions of ER stress in Wolfram syndrome and other forms of diabetes. American Diabetes Association 2014-03 2014-02-13 /pmc/articles/PMC3931392/ /pubmed/24227685 http://dx.doi.org/10.2337/db13-0717 Text en © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. |
spellingShingle | Metabolism Shang, Linshan Hua, Haiqing Foo, Kylie Martinez, Hector Watanabe, Kazuhisa Zimmer, Matthew Kahler, David J. Freeby, Matthew Chung, Wendy LeDuc, Charles Goland, Robin Leibel, Rudolph L. Egli, Dieter β-Cell Dysfunction Due to Increased ER Stress in a Stem Cell Model of Wolfram Syndrome |
title | β-Cell Dysfunction Due to Increased ER Stress in a Stem Cell Model of Wolfram Syndrome |
title_full | β-Cell Dysfunction Due to Increased ER Stress in a Stem Cell Model of Wolfram Syndrome |
title_fullStr | β-Cell Dysfunction Due to Increased ER Stress in a Stem Cell Model of Wolfram Syndrome |
title_full_unstemmed | β-Cell Dysfunction Due to Increased ER Stress in a Stem Cell Model of Wolfram Syndrome |
title_short | β-Cell Dysfunction Due to Increased ER Stress in a Stem Cell Model of Wolfram Syndrome |
title_sort | β-cell dysfunction due to increased er stress in a stem cell model of wolfram syndrome |
topic | Metabolism |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931392/ https://www.ncbi.nlm.nih.gov/pubmed/24227685 http://dx.doi.org/10.2337/db13-0717 |
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