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Discovery of a drug candidate for GLIS3-associated diabetes

Author

Listed:
  • Sadaf Amin

    (Weill Graduate School of Medical Sciences of Cornell University
    Department of Surgery)

  • Brandoch Cook

    (Department of Surgery)

  • Ting Zhou

    (Department of Surgery)

  • Zaniar Ghazizadeh

    (Department of Surgery)

  • Raphael Lis

    (Ansary Stem Cell Institute)

  • Tuo Zhang

    (Genomics Resources Core Facility)

  • Mona Khalaj

    (Weill Graduate School of Medical Sciences of Cornell University
    Memorial Sloan Kettering Cancer Center)

  • Miguel Crespo

    (Department of Surgery)

  • Manuradhi Perera

    (Department of Surgery)

  • Jenny Zhaoying Xiang

    (Genomics Resources Core Facility)

  • Zengrong Zhu

    (Sloan Kettering Institute)

  • Mark Tomishima

    (Sloan Kettering Institute
    Sloan Kettering Institute)

  • Chengyang Liu

    (University of Pennsylvania School of Medicine)

  • Ali Naji

    (University of Pennsylvania School of Medicine)

  • Todd Evans

    (Department of Surgery)

  • Danwei Huangfu

    (Sloan Kettering Institute)

  • Shuibing Chen

    (Weill Graduate School of Medical Sciences of Cornell University
    Department of Surgery
    Weill Cornell Medicine)

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.

Suggested Citation

  • 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, 2018. "Discovery of a drug candidate for GLIS3-associated diabetes," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04918-x
    DOI: 10.1038/s41467-018-04918-x
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    Cited by:

    1. Xiaojie Ma & Jie Cao & Ziyu Zhou & Yunkun Lu & Qin Li & Yan Jin & Guo Chen & Weiyun Wang & Wenyan Ge & Xi Chen & Zhensheng Hu & Xiao Shu & Qian Deng & Jiaqi Pu & Chengzhen Liang & Junfen Fu & Jianzhao, 2022. "N6-methyladenosine modification-mediated mRNA metabolism is essential for human pancreatic lineage specification and islet organogenesis," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Yue Liu & Yue Yang & Chenying Xu & Jianxing Liu & Jiale Chen & Guoqing Li & Bin Huang & Yi Pan & Yanfeng Zhang & Qiong Wei & Stephen J. Pandol & Fangfang Zhang & Ling Li & Liang Jin, 2023. "Circular RNA circGlis3 protects against islet β-cell dysfunction and apoptosis in obesity," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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