β-cell dysfunction due to increased ER stress in a stem cell model of wolfram syndrome

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

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)923-933
Number of pages11
JournalDiabetes
Volume63
Issue number3
DOIs
StatePublished - Mar 2014
Externally publishedYes

Fingerprint Dive into the research topics of 'β-cell dysfunction due to increased ER stress in a stem cell model of wolfram syndrome'. Together they form a unique fingerprint.

Cite this