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Discovery of a drug candidate for GLIS3-associated diabetes

Sadaf Amin1,2, Brandoch Cook2, Ting Zhou2

  • 1Weill Graduate School of Medical Sciences of Cornell University, 1300 York Avenue, New York, NY, 10065, USA.

Nature Communications
|July 12, 2018
PubMed

Insights

Genetic mutations in GLIS3 disrupt pancreatic beta cell function, leading to various diabetes types. This study identifies a drug candidate that rescues GLIS3-deficient beta cell death by targeting the TGFβ pathway.

Area of Science:

  • Endocrinology and Diabetes Research
  • Stem Cell Biology
  • Genetics and Genomics

Background:

  • GLIS3 mutations are linked to diverse diabetes forms (type 1, type 2, neonatal), highlighting its crucial role in pancreatic beta cell function.
  • Previous studies failed to replicate GLIS3-related beta cell defects using GLIS3 knockout (GLIS3-/-) beta-like cells.

Purpose of the Study:

  • To develop an optimized protocol for generating functional human pancreatic beta-like cells from stem cells.
  • To investigate the impact of GLIS3 deficiency on pancreatic progenitor and beta-like cell development and survival.
  • To identify therapeutic strategies for GLIS3-associated diabetes.

Main Methods:

  • Developed a "minimal component" protocol to generate late-stage pancreatic progenitors (PP2) and subsequently mono-hormonal glucose-responding beta-like (PP2-β) cells from human embryonic stem cells (hESCs).
  • Utilized this platform to study GLIS3-/- hESCs differentiation and cell viability.
  • Conducted a high-content chemical screen to identify potential therapeutic compounds.
  • Investigated the molecular mechanisms underlying GLIS3 loss-induced beta cell death, focusing on the TGFβ pathway.

Main Results:

  • GLIS3-/- hESCs exhibited impaired differentiation, characterized by significant death of PP2 and PP2-β cells, without affecting the overall endocrine cell population.
  • A drug candidate was identified that effectively rescued GLIS3-mutant beta cell death in both in vitro and in vivo models.
  • Loss of GLIS3 was found to induce beta cell death through the activation of the TGFβ signaling pathway.

Conclusions:

  • Established an optimized directed differentiation protocol for modeling human beta cell diseases, including GLIS3-associated diabetes.
  • Identified a promising drug candidate capable of rescuing GLIS3-deficient beta cell loss, offering a potential therapeutic avenue for a wide range of diabetic patients.
  • Elucidated the mechanism of GLIS3-associated beta cell death, involving TGFβ pathway activation.

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