1. β-cell dysfunction due to increased ER stress in a stem cell model of Wolfram syndrome
- Author
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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., and Egli, Dieter
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Ear diseases -- Physiological aspects ,Cell research ,Pancreatic beta cells -- Physiological aspects ,Cellular control mechanisms -- Research ,Health - 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. Diabetes 2014;63:923-933 | DOI: 10.2337/db13-0717, All forms of diabetes are ultimately the result of an inability of pancreatic β-cells to provide sufficient insulin in response to ambient blood glucose concentrations. Stem cell-based models of diabetes [...]
- Published
- 2014
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