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.