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

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 individu...

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Veröffentlicht in:Diabetes (New York, N.Y.) N.Y.), 2014-03, Vol.63 (3), p.923-933
Hauptverfasser: LINSHAN SHANG, HAIQING HUA, GOLAND, Robin, LEIBEL, Rudolph L, EGLI, Dieter, FOO, Kylie, MARTINEZ, Hector, WATANABE, Kazuhisa, ZIMMER, Matthew, KAHLER, David J, FREEBY, Matthew, WENDY CHUNG, LEDUC, Charles
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Sprache:eng
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Zusammenfassung: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.
ISSN:0012-1797
1939-327X
DOI:10.2337/db13-0717