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Discovery of a Drug Candidate for GLIS3-associated Diabetes

Discovery of a Drug Candidate for GLIS3-associated Diabetes

Sadaf Amin, Brandoch Cook, Ting Zhou, Zaniar Ghazizadeh, Raphael Lis, Tuo Zhang, Mona Khalaj, Miguel Crespo, Manuradhi Perera, Jenny Zhaoying Xiang, Zengrong Zhu, Mark Tomishima, Chengyang Liu, Ali Naji, etc.

Nat Commun. 2018 Jul 11;9(1):2681.

PMID: 29992946

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4241783	PP2			Price

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