GABA and Artesunate Do Not Induce Pancreatic α-to-β Cell Transdifferentiation In Vivo

Recent reports identified activation of the GABA signaling pathway as a means to induce transdifferentiation of pancreatic alpha cells into beta cells. These reports followed several previous studies that found that alpha cells were particularly well suited to conversion into beta cells in mice, but only after nearly complete beta cell loss or forced overexpression of key transcriptional regulators. The possibility of increasing beta cell number via reprograming of alpha cells with a small molecule is enticing, as this could be a potential new pharmacologic therapy for diabetes. Here, we employed rigorous genetic lineage tracing of alpha cells, using Glucagon-CreER(T2); Rosa-LSL-eYFP mice, to evaluate if activation of GABA signaling caused alpha-to-beta cell reprogramming. In contrast to previous reports, we found that even after long-term treatment of mice with artesunate or GABA, neither alpha-to-beta cell transdifferentiation nor insulin secretion were stimulated, putting into question whether these agents represent a viable path to a novel diabetes therapy.