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Discovery of a drug candidate for GLIS3-associated diabetes.

TitleDiscovery of a drug candidate for GLIS3-associated diabetes.
Publication TypeJournal Article
Year of Publication2018
AuthorsAmin, S, Cook, B, Zhou, T, Ghazizadeh, Z, Lis, R, Zhang, T, Khalaj, M, Crespo, M, Perera, M, Xiang, JZhaoying, Zhu, Z, Tomishima, M, Liu, C, Naji, A, Evans, T, Huangfu, D, Chen, S
JournalNat Commun
Date Published2018 07 11
KeywordsAnimals, Cell Differentiation, Cell Line, Diabetes Mellitus, Drug Discovery, Gene Expression Profiling, Human Embryonic Stem Cells, Humans, Hypoglycemic Agents, Insulin Secretion, Insulin-Secreting Cells, Male, Mice, SCID, Mutation, Pyrazoles, Quinolines, Transcription Factors, Transplantation, Heterologous

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.

Alternate JournalNat Commun
PubMed ID29992946
PubMed Central IDPMC6041295
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
R01 DK096239 / DK / NIDDK NIH HHS / United States
DP3 DK111907-01 / / U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases) / International