An Isogenic Human ESC Platform for Functional Evaluation of Genome-wide-Association-Study-Identified Diabetes Genes and Drug Discovery

Cell Stem Cell. 2016 Sep 1;19(3):326-40. doi: 10.1016/j.stem.2016.07.002. Epub 2016 Aug 11.


Genome-wide association studies (GWASs) have increased our knowledge of loci associated with a range of human diseases. However, applying such findings to elucidate pathophysiology and promote drug discovery remains challenging. Here, we created isogenic human ESCs (hESCs) with mutations in GWAS-identified susceptibility genes for type 2 diabetes. In pancreatic beta-like cells differentiated from these lines, we found that mutations in CDKAL1, KCNQ1, and KCNJ11 led to impaired glucose secretion in vitro and in vivo, coinciding with defective glucose homeostasis. CDKAL1 mutant insulin+ cells were also hypersensitive to glucolipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1-specific defects in vitro and in vivo by inhibiting the FOS/JUN pathway. Our approach of a proof-of-principle platform, which uses isogenic hESCs for functional evaluation of GWAS-identified loci and identification of a drug candidate that rescues gene-specific defects, paves the way for precision therapy of metabolic diseases.

Publication types

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

MeSH terms

  • Alleles
  • Animals
  • Benzophenones / pharmacology
  • Biomarkers / metabolism
  • CRISPR-Cas Systems / genetics
  • Cell Line
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / pathology
  • Drug Discovery*
  • Gene Targeting
  • Genome-Wide Association Study*
  • Glucose / toxicity
  • Green Fluorescent Proteins / metabolism
  • Homeostasis / drug effects
  • Human Embryonic Stem Cells / cytology
  • Human Embryonic Stem Cells / drug effects
  • Human Embryonic Stem Cells / metabolism*
  • Humans
  • Insulin / metabolism
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Isoxazoles / pharmacology
  • KCNQ1 Potassium Channel / genetics
  • Lipids / toxicity
  • Mice
  • Mutation / genetics
  • Potassium Channels, Inwardly Rectifying / genetics
  • Signal Transduction / drug effects
  • tRNA Methyltransferases / genetics


  • 3-(5-(4-(cyclopentyloxy)-2-hydroxybenzoyl)-2-((3-hydroxy-1,2-benzisoxazol-6-yl)methoxy)phenyl)propionic acid
  • Benzophenones
  • Biomarkers
  • Insulin
  • Isoxazoles
  • KCNQ1 Potassium Channel
  • KCNQ1 protein, human
  • Kir6.2 channel
  • Lipids
  • Potassium Channels, Inwardly Rectifying
  • Green Fluorescent Proteins
  • tRNA Methyltransferases
  • CDKAL1 protein, human
  • Glucose