Lifelong insulin replacement remains the mainstay of type 1 diabetes treatment. Genetic FoxO1 ablation promotes enteroendocrine cell (EECs) conversion into glucose-responsive β-like cells. Here, we tested whether chemical FoxO1 inhibitors can generate β-like gut cells. Pan-intestinal epithelial FoxO1 ablation expanded the EEC pool, induced β-like cells, and improved glucose tolerance in Ins2Akita/+ mice. This genetic effect was phenocopied by small molecule FoxO1 inhibitor, Cpd10. Cpd10 induced β-like cells that released insulin in response to glucose in mouse gut organoids, and this effect was strengthened by the Notch inhibitor, DBZ. In Ins2Akita/+ mice, a five-day course of either Cpd10 or DBZ induced insulin-immunoreactive β-like cells in the gut, lowered glycemia, and increased plasma insulin levels without apparent adverse effects. These results provide proof of principle of gut cell conversion into β-like cells by a small molecule FoxO1 inhibitor, paving the way for clinical applications.

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