β-Cell Dysfunction Due to Increased ER Stress in a Stem Cell Model of Wolfram Syndrome
- Linshan Shang1,
- Haiqing Hua1,2,
- Kylie Foo2,
- Hector Martinez1,
- Kazuhisa Watanabe2,
- Matthew Zimmer1,
- David J. Kahler1,
- Matthew Freeby2,
- Wendy Chung2,
- Charles LeDuc2,
- Robin Goland2,
- Rudolph L. Leibel2 and
- Dieter Egli1⇑
- 1The New York Stem Cell Foundation Research Institute, New York, NY
- 2Division of Molecular Genetics, Department of Pediatrics and Naomi Berrie Diabetes Center, Columbia University, New York, NY
- Corresponding author: Dieter Egli, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0717/-/DC1.
See accompanying article, p. 844.
- Received May 3, 2013.
- Accepted November 6, 2013.
- © 2014 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.