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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container_end_page 933
container_issue 3
container_start_page 923
container_title Diabetes (New York, N.Y.)
container_volume 63
creator 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
description 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.
doi_str_mv 10.2337/db13-0717
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source Journals@Ovid Ovid Autoload; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central
subjects Animals
Biological and medical sciences
Calcium - metabolism
Cell Differentiation
Cell research
Cellular control mechanisms
Complex syndromes
Diabetes. Impaired glucose tolerance
Ear diseases
Endocrine pancreas. Apud cells (diseases)
Endocrinopathies
Endoplasmic Reticulum Stress
Etiopathogenesis. Screening. Investigations. Target tissue resistance
Humans
Induced Pluripotent Stem Cells - cytology
Insulin - biosynthesis
Insulin - metabolism
Insulin Secretion
Insulin-Secreting Cells - physiology
Medical genetics
Medical sciences
Membrane Proteins - genetics
Metabolism
Mice
Pancreatic beta cells
Phenylbutyrates - pharmacology
Physiological aspects
Wolfram Syndrome - genetics
Wolfram Syndrome - pathology
title β-Cell Dysfunction Due to Increased ER Stress in a Stem Cell Model of Wolfram Syndrome
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