Journal
CELL
Volume 168, Issue 1-2, Pages 86-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2016.11.010
Keywords
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Categories
Funding
- JDRF award [31-2012-783, 1-RSC-2014-100-I-X, 3-SRA-2015-20-Q-R, 17-2011-258]
- NIDDK [1UC4DK098085]
- European Research Council [ERC-2015-AdG-695136, StG-2011-281265]
- Medical University of Vienna
- EMBO long-term research fellowship [ALTF 596-2014]
- NovoNordisk Foundation
- European Commission [GA-2012-600394]
- Austrian Science Fund [FWF P25659-B19]
- DOC Fellowship of the Austrian Academy of Sciences
- INSERM AVENIR program
- INSERM
- FMR [DRC20091217179]
- ANR/BMBF [2009 GENO 105 01/01KU0906]
- Investments for the Future'' LABEX SIGNALIFE [ANR-11-LABX-0028-01]
- Max-Planck Society
- Club Isatis
- Fondation Generale de Sante
- Foundation Schlumberger pour l'Education et la Recherche
- New Frontiers Research Infrastructure grant from the Austrian Academy of Sciences
- Austrian Federal Ministry of Science, Research and Economy
- National Foundation for Research, Technology, and Development
- GW Pharmaceuticals
- [17-2011-16]
- [2-2010-567]
- [26-2008-639]
- [17-2013-426]
- [3-PDF-2014-206-A-N]
- Alzheimers Research UK [ART-EG2009A-1] Funding Source: researchfish
- Novo Nordisk Fonden [NNF14OC0010695, NNF15OC0015964, NNF17OC0027294] Funding Source: researchfish
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Type 1 diabetes is characterized by the destruction of pancreatic beta cells, and generating new insulin-producing cells from other cell types is a major aim of regenerative medicine. One promising approach is transdifferentiation of developmentally related pancreatic cell types, including glucagon-producing a cells. In a genetic model, loss of the master regulatory transcription factor Arx is sufficient to induce the conversion of a cells to functional beta-like cells. Here, we identify artemisinins as small molecules that functionally repress Arx by causing its translocation to the cytoplasm. We show that the protein gephyrin is the mammalian target of these antimalarial drugs and that the mechanism of action of these molecules depends on the enhancement of GABA(A) receptor signaling. Our results in zebrafish, rodents, and primary human pancreatic islets identify gephyrin as a druggable target for the regeneration of pancreatic b cell mass from alpha cells.
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