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

  1. Dieter Egli1
  1. 1The New York Stem Cell Foundation Research Institute, New York, NY
  2. 2Division of Molecular Genetics, Department of Pediatrics and Naomi Berrie Diabetes Center, Columbia University, New York, NY
  1. Corresponding author: Dieter Egli, d.egli{at}nyscf.org.

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.

Footnotes

  • Received May 3, 2013.
  • Accepted November 6, 2013.

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  1. Diabetes vol. 63 no. 3 923-933
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