| First Author | Shang L | Year | 2014 |
| Journal | Diabetes | Volume | 63 |
| Issue | 3 | Pages | 923-33 |
| PubMed ID | 24227685 | Mgi Jnum | J:208989 |
| Mgi Id | MGI:5565527 | Doi | 10.2337/db13-0717 |
| Citation | Shang L, et al. (2014) beta-cell dysfunction due to increased ER stress in a stem cell model of Wolfram syndrome. Diabetes 63(3):923-33 |
| abstractText | 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 beta-cell failure, we used induced pluripotent stem cells to create insulin-producing cells from individuals with Wolfram syndrome. WFS1-deficient beta-cells showed increased levels of endoplasmic reticulum (ER) stress molecules and decreased insulin content. Upon exposure to experimental ER stress, Wolfram beta-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 beta-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. |
