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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 ?-cell biology. Previous attempts to recapitulate disease-relevant phenotypes in GLIS3-/- ?-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 ?-like (PP2-?) cells. Using this differentiation platform, we discover that GLIS3-/- hESCs show impaired differentiation, with significant death of PP2 and PP2-? 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 ?-cell death both in vitro and in vivo. Finally, we discovered that loss of GLIS3 causes ?-cell death, by activating the TGF? pathway. This study establishes an optimized directed differentiation protocol for modeling human ?-cell disease and identifies a drug candidate for treating a broad range of GLIS3-associated diabetic patients.

SUBMITTER: Amin S

PROVIDER: S-EPMC6041295 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Discovery of a drug candidate for GLIS3-associated diabetes.

Amin Sadaf S Cook Brandoch B Zhou Ting T Ghazizadeh Zaniar Z Lis Raphael R Zhang Tuo T Khalaj Mona M Crespo Miguel M Perera Manuradhi M Xiang Jenny Zhaoying JZ Zhu Zengrong Z Tomishima Mark M Liu Chengyang C Naji Ali A Evans Todd T Huangfu Danwei D Chen Shuibing S

Nature communications 20180711 1

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<sup>-/-</sup> 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 GL ...[more]

PMID: 29992946

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Project description:A robust system using disease relevant cells to systematically evaluate the role in diabetes for loci identified through genome wide association studies (GWAS) is urgently needed. Toward this goal, we created isogenic mutant human embryonic stem cell (hESC) lines in GWAS-identified candidate diabetes genes including CDKAL1, KCNQ1 and KCNJ11, and used directed differentiation to evaluate the function of derivative human beta-like cells. The mutations did not affect the generation of insulin+ cells, but impaired insulin secretion both in vitro and in vivo, coinciding with defective glucose homeostasis. CDKAL1-/- insulin+ cells also displayed hypersensitivity to lipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1-/--specific defects by inhibiting the AP1 (FOS/JUN) pathway. These studies establish a platform using isogenic hESCs to evaluate the function of GWAS-identified loci, and identify a drug candidate that rescues gene-specific defects, paving the way to precision therapy of metabolic diseases.A robust system using disease relevant cells to systematically evaluate the role in diabetes for loci identified through genome wide association studies (GWAS) is urgently needed. Toward this goal, we created isogenic mutant human embryonic stem cell (hESC) lines in GWAS-identified candidate diabetes genes including CDKAL1, KCNQ1 and KCNJ11, and used directed differentiation to evaluate the function of derivative human beta-like cells. The mutations did not affect the generation of insulin+ cells, but impaired insulin secretion both in vitro and in vivo, coinciding with defective glucose homeostasis. CDKAL1-/- insulin+ cells also displayed hypersensitivity to lipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1-/--specific defects by inhibiting the AP1 (FOS/JUN) pathway. These studies establish a platform using isogenic hESCs to evaluate the function of GWAS-identified loci, and identify a drug candidate that rescues gene-specific defects, paving the way to precision therapy of metabolic diseases.

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Discovery of a drug candidate for GLIS3-associated diabetes.

Publications

Discovery of a drug candidate for GLIS3-associated diabetes.

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