Type 1 diabetes is characterized by the destruction of pancrea  tic 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  alpha  cells.  In  a  genetic  model,  loss  of  the  master regulatory  transcription  factor  Arx   is sufficient  to  induce  the  conversion  of  alpha  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  antimalaria  drugs, and  that  enhancement  of  GABAA receptor  signaling  contributes  to  the  mechanism of  action of  these  molecules  in  pancreatic   transdifferentiation.  Our  results  in  zebrafish,  rodents  and  primary  human  pancreatic  islets indicate that gephyrin is a novel druggable target for the regeneration of pancreatic beta cell mass from alpha cells. SOURCE: Jin Li (jli21@bidmc.harvard.edu) -  BIDMC

Pluto Bioinformatics

GSE84592: Artemisinins target GABAA receptor signaling and impair alpha cell identity