Final Report Summary - BETAREGENERATION (Induction of Insulin-producing beta-cells Regeneration in vivo)
Type 1 diabetes is an auto-immune disease characterized by the selective destruction of insulin-secreting beta-cells leading to chronic hyperglycemia. The latter, when poorly managed, can result in severe complications, including cardiovascular complications, blindness or amputation. The constantly increasing number of diabetic patients associated with the highly restrictive aspects of current therapies (mainly daily exogenous insulin injections) call for the establishment of novel strategies. Most current research efforts therefore aim at finding way to (re)generate insulin-producing cells by mimicking beta-cell (neo)genesis.Towards this goal, 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 alpha cell replacement mechanisms through the mobilization of precursor cells that adopt an alpha cell identity prior to being converted into beta-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 alpha 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.