Journal
CELL STEM CELL
Volume 19, Issue 3, Pages 326-340Publisher
CELL PRESS
DOI: 10.1016/j.stem.2016.07.002
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Funding
- New York Stem Cell Foundation [R-103]
- American Diabetes Association [1-12-JF-06]
- Tri-institutional Starr Stem Cell Grant [2014-030]
- NYSTEM postdoctoral fellowship
- NIH [HL078960]
- AHA [16GRNT26430113]
- Biomedical Research Program funds at Weill Cornell Medical College in Qatar - Qatar Foundation
- NHLBI [K01HL129892]
- New York State Department of Health [NYSTEM C029156]
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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.
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