Discovery of a drug candidate for GLIS3-associated diabetes Journal Article
| Authors: | Amin, S.; Cook, B.; Zhou, T.; Ghazizadeh, Z.; Lis, R.; Zhang, T.; Khalaj, M.; Crespo, M.; Perera, M.; Xiang, J. Z.; Zhu, Z.; Tomishima, M.; Liu, C.; Naji, A.; Evans, T.; Huangfu, D.; Chen, S. |
| Article Title: | Discovery of a drug candidate for GLIS3-associated diabetes |
| Abstract: | GLIS3 mutations are associated with type 1, type 2, and neonatal diabetes, reflecting a key function for this gene in pancreatic β-cell biology. Previous attempts to recapitulate disease-relevant phenotypes in GLIS3 -/- β-like cells have been unsuccessful. Here, we develop a "minimal component" protocol to generate late-stage pancreatic progenitors (PP2) that differentiate to mono-hormonal glucose-responding β-like (PP2-β) cells. Using this differentiation platform, we discover that GLIS3 -/- hESCs show impaired differentiation, with significant death of PP2 and PP2-β cells, without impacting the total endocrine pool. Furthermore, we perform a high-content chemical screen and identify a drug candidate that rescues mutant GLIS3-associated β-cell death both in vitro and in vivo. Finally, we discovered that loss of GLIS3 causes β-cell death, by activating the TGFβ pathway. This study establishes an optimized directed differentiation protocol for modeling human β-cell disease and identifies a drug candidate for treating a broad range of GLIS3-associated diabetic patients. © 2018 The Author(s). |
| Journal Title: | Nature Communications |
| Volume: | 9 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2018-07-11 |
| Start Page: | 2681 |
| Language: | English |
| DOI: | 10.1038/s41467-018-04918-x |
| PROVIDER: | scopus |
| PMCID: | PMC6041295 |
| PUBMED: | 29992946 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 August 2018 -- Source: Scopus |
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