β-Cell Dysfunction Due to Increased ER Stress in a Stem Cell Model of Wolfram Syndrome

نویسندگان

  • 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
چکیده

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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عنوان ژورنال:

دوره 63  شماره 

صفحات  -

تاریخ انتشار 2014