Long-Term GABA Administration Induces Alpha Cell-Mediated Beta-like Cell Neogenesis

The recent discovery that genetically modified alpha cells can regenerate and convert into beta-like cells in vivo holds great promise for diabetes research. However, to eventually translate these findings to human, it is crucial to discover compounds with similar activities. Herein, we report the identification of GABA as an inducer of alpha-to- beta-like cell conversion in vivo. This conversion induces a cell replacement mechanisms through the mobilization of duct-lining precursor cells that adopt an a cell identity prior to being converted into b-like cells, solely upon sustained GABA exposure. Importantly, these neo-generated beta-like cells are functional and can repeatedly reverse chemically induced diabetes in vivo. Similarly, the treatment of transplanted human islets with GABA results in a loss of a cells and a concomitant increase in beta- like cell counts, suggestive of alpha-to-beta- like cell conversion processes also in humans. This newly discovered GABA-induced alpha cell-mediated beta-like cell neogenesis could therefore represent an unprecedented hope toward improved therapies for diabetes.