A delta-cell subpopulation with a pro-beta-cell identity contributes to efficient age-independent recovery in a zebrafish model of diabetes

Restoring damaged beta-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 Insulin-expressing cells. To overcome the weak regenerative capacity of mammals, we used regeneration-prone zebrafish to study beta-cells arising following destruction. We show that most new insulin cells differ from the original beta-cells as they coexpress Somatostatin and Insulin. These bihormonal cells are abundant, functional and able to normalize glycemia. Their formation in response to beta-cell destruction is fast, efficient, and age-independent. Bihormonal cells are transcriptionally close to a subset of delta-cells that we identified in control islets and that are characterized by the expression of somatostatin 1.1 (sst1.1) and by genes essential for glucose-induced Insulin secretion in beta-cells such as pdx1, slc2a2 and gck. We observed in vivo the conversion of monohormonal sst1.1-expressing cells to sst1.1+ ins + bihormonal cells following beta-cell destruction. Our findings support the conclusion that sst1.1 delta-cells possess a pro-beta 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.