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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2014
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.
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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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