Background and purpose: Recently, the anti-malarial drug, artemether, and the neurotransmitter γ-aminobutyric acid (GABA) were identified to convert α cells into β-like cells in vivo. However, some of these observations were challenged by other studies. To help address the controversy, we took advantage of zebrafish as a model to perform this study.

Experimental approach: Firstly, we performed a small molecule screening for artemether and its skeleton analogs. Secondly, we used the Cre-LoxP system for lineage tracing to indicate the conversion of α cells into β cells in vivo. The stable transgenic ins2:eGFP αTC1-6 cell line were used for evaluation of α cell transdifferentiation in vitro. We further used multiple zebrafish transgenic and mutation lines to demonstrate β-cell differentiation, β-cell ablation and α-cell hyperplasia in this study.

Key results: We showed that artemether and another sesquiterpene, aspterric acid, induced α cell transdifferentiation into β cells, both in zebrafish as well as using αTC1-6 cells. Furthermore, these two compounds also converted α cells into β cells when β cells were lost or α cells were hyperplastic in zebrafish. Unlike the previous report, the conversion of α cells to β cells was mediated by increasing Pax4 expression, but not suppression of Arx expression.

Conclusions and implications: Our data suggest that in zebrafish and αTC1-6 cells, both artemether and aspterric acid induce α cell transdifferentiation. Our data, along with those of Li et al. (2017), suggested that artemether and aspterric acid were able to induce α cell transdifferentiation, at least in zebrafish and αTC1-6 cells.