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

Abstract

Recent reports identified activation of the GABA signaling pathway as a means to induce transdifferentiation of pancreatic α cells into β cells. These reports followed several previous studies that found that α cells were particularly well suited to conversion into β cells in mice, but only after nearly complete β cell loss or forced overexpression of key transcriptional regulators. The possibility of increasing β cell number via reprograming of α 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 α cells, using Glucagon-CreER^T2;Rosa-LSL-eYFP mice, to evaluate if activation of GABA signaling caused α-to-β cell reprogramming. In contrast to previous reports, we found that even after long-term treatment of mice with artesunate or GABA, neither α-to-β cell transdifferentiation nor insulin secretion were stimulated, putting into question whether these agents represent a viable path to a novel diabetes therapy.

Keywords: artemisinin; diabetes; islets of Langerhans; pancreatic alpha cell; pancreatic beta cell; transdifferentiation.