Artemether And Aspterric Acid Induces Pancreatic α Cells Transdifferentiate Into β Cells In Zebrafish

Pancreatic β-cell deficiency is a major feature of type 1 diabetes and it is common in late-stage type 2 diabetes mellitus.Thus,development of strategies for β-cell restoration would be highly beneficial.Recently,the anti-malarial drug,artemether,and the neurotransmitter y-aminobutyric acid(GABA)were identified to convert α cells into β-like cells in vivo.It is enticing that regeneration of β cells,via reprogramming ofα cells with a small molecule,could be a potential strategy for diabetes therapy.However,some of these observations were queried by the following studies.Because the reported compound artemether belongs to the sesquiterpene,and it has been confirmed that sesquiterpenes especially sesquiterpene lactones could prevent or delay the progress of diabetes.In this study,we selected some diterpenes or sesquiterpenes which were isolated from natural products in our laboratory.Taking advantage of transgenic zebrafish,their activity in inducing a cell transdifferentiation was screened.Finally,we found that the small molecule aspterric acid could induce a cell convert into β cell.At the same time,we evaluated the activity of artemether and GABA,and found that aspterric acid works similarly with artemether in the conversion of α cells into β cells.Moreover,artemether and aspterric acid were able to induce a cell transdifferentiation in β cell ablated diabetic model or a cell hyperplasia model.More importantly,unlike the previous report,we found that the conversion of a cell toβ cell was mediated by increasing Pax4 expression,but not suppression of Arx expression.As for GABA,we found it could induce the differentiation of endocrine precursor cells.These results stand in line with some studies published before,and confirmed the feasibility of molecule induced a to β cell conversion,which provided a new strategy in β cell regeneration.