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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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Detalles Bibliográficos
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
Descripción
Sumario: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.