β-cell dysfunction due to increased ER stress in a stem cell model of Wolfram syndrome.
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| Abstract |
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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| Authors | Linshan Shang, Haiqing Hua, Kylie Foo, Hector Martinez, Kazuhisa Watanabe, Matthew Zimmer, David J Kahler, Matthew Freeby, Wendy Chung, Charles LeDuc, Robin Goland, Rudolph L Leibel, Dieter Egli |
| Journal | Diabetes (Diabetes) Vol. 63 Issue 3 Pg. 923-33 (Mar 2014) ISSN: 1939-327X [Electronic] United States |
| PMID | 24227685 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't) |
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