Generation of functional insulin-producing cells in the gut by Foxo1 ablation

Restoration of regulated insulin secretion is the ultimate goal of therapy for type 1 diabetes. Here, we show that, unexpectedly, somatic ablation of Foxo1 in Neurog3 ⁺ enteroendocrine progenitor cells gives rise to gut insulin-positive (Ins ⁺) cells that express markers of mature β cells and secrete bioactive insulin as well as C-peptide in response to glucose and sulfonylureas. Lineage tracing experiments showed that gut Ins ⁺ cells arise cell autonomously from Foxo1-deficient cells. Inducible Foxo1 ablation in adult mice also resulted in the generation of gut Ins ⁺ cells. Following ablation by the β-cell toxin streptozotocin, gut Ins ⁺ cells regenerate and produce insulin, reversing hyperglycemia in mice. The data indicate that Neurog3 ⁺ enteroendocrine progenitors require active Foxo1 to prevent differentiation into Ins ⁺ cells. Foxo1 ablation in gut epithelium may provide an approach to restore insulin production in type 1 diabetes.