Cell doi:10.1016/j.cell.2016.11.010 (2016)

Cellular plasticity can be induced in pancreatic cell types and results in trans-differentiation. Forced overexpression of the transcription factor Pax4 is sufficient to convert alpha (α) cells into beta (β) cells, while overexpression of the transcription factor Arx does the opposite to reduce insulin production. Li et al. performed a chemical screen to identify small molecules that could reverse Arx-mediated conversion of β cells into α cells and enable production of insulin. Their leading candidate was artemether, a known compound that is used to treat malaria but has no defined cellular target, as a promoter of β-cell identity due to inhibition of Arx nuclear localization. Chemoproteomic analysis using cellular pulldowns and MS analysis revealed that artemether directly interacted with gephyrin and promoted its stability. Gephryin, which is known to transport GABAA receptors to the membrane, stimulates GABAA-receptor-mediated cellular Cl influx that enables blocking of glucagon secretion in α cells, which results in the loss of α-cell identity. Artemether treatment in a zebrafish β-cell ablation model, wild-type mice and human islets increased pancreatic β-cell size and number and upregulated insulin expression and secretion in α cells. Future studies will need to mechanistically connect the upregulation of GABA signaling with the loss of ARX nuclear localization.