A δ-cell Subpopulation with a Pro-β-cell Identity Contributes to Efficient Age-independent Recovery in a Zebrafish Model of Diabetes

Restoring damaged β-cells in diabetic patients by harnessing the plasticity of other pancreatic cells raises the questions of the efficiency of the process and of the functionality of the new -expressing cells. To overcome the weak regenerative capacity of mammals, we used regeneration-prone zebrafish to study β-cells arising following destruction. We show that most new s cells differ from the original β-cells as they coexpress Somatostatin and Insulin. These bihormonal cells are abundant, functional and able to normalize glycemia. Their formation in response to β-cell destruction is fast, efficient, and age-independent. Bihormonal cells are transcriptionally close to a subset of δ-cells that we identified in control islets and that are characterized by the expression of () and by genes essential for glucose-induced Insulin secretion in β-cells such as , s and . We observed in vivo the conversion of monohormonal expressing cells to + bihormonal cells following β-cell destruction. Our findings support the conclusion that δ-cells possess a pro-β identity enabling them to contribute to the neogenesis of Insulin-producing cells during regeneration. This work unveils that abundant and functional bihormonal cells benefit to diabetes recovery in zebrafish.