RT Journal Article SR Electronic T1 β-Cell Dysfunction Due to Increased ER Stress in a Stem Cell Model of Wolfram Syndrome JF Diabetes JO Diabetes FD American Diabetes Association SP 923 OP 933 DO 10.2337/db13-0717 VO 63 IS 3 A1 Shang, Linshan A1 Hua, Haiqing A1 Foo, Kylie A1 Martinez, Hector A1 Watanabe, Kazuhisa A1 Zimmer, Matthew A1 Kahler, David J. A1 Freeby, Matthew A1 Chung, Wendy A1 LeDuc, Charles A1 Goland, Robin A1 Leibel, Rudolph L. A1 Egli, Dieter YR 2014 UL http://diabetes.diabetesjournals.org/content/63/3/923.abstract AB 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.