Discovery of a drug candidate for GLIS3-associated diabetes

Nat Commun. 2018 Jul 11;9(1):2681. doi: 10.1038/s41467-018-04918-x.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Cell Line
  • DNA-Binding Proteins
  • Diabetes Mellitus / genetics
  • Diabetes Mellitus / metabolism
  • Diabetes Mellitus / prevention & control*
  • Drug Discovery / methods*
  • Gene Expression Profiling
  • Human Embryonic Stem Cells / cytology
  • Human Embryonic Stem Cells / metabolism
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology
  • Male
  • Mice, SCID
  • Mutation
  • Pyrazoles / pharmacology
  • Quinolines / pharmacology
  • Repressor Proteins
  • Trans-Activators
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transplantation, Heterologous


  • DNA-Binding Proteins
  • GLIS3 protein, human
  • Hypoglycemic Agents
  • Pyrazoles
  • Quinolines
  • Repressor Proteins
  • Trans-Activators
  • Transcription Factors
  • LY-2157299