Chemical induction of gut β-like-cells by combined FoxO1/Notch inhibition as a glucose-lowering treatment for diabetes

Lifelong insulin replacement remains the mainstay of type 1 diabetes treatment. Genetic FoxO1 ablation promotes enteroendocrine cell (EECs) conversion into glucose-responsive {beta}-like cells. Here, we tested whether chemical FoxO1 inhibitors can generate {beta}-like gut cells. Pan-intestinal epithelial FoxO1 ablation expanded the EEC pool, induced {beta}-like cells, and improved glucose tolerance in Ins2Akita/+ mice. This genetic effect was phenocopied by small molecule FoxO1 inhibitor, Cpd10. Cpd10 induced {beta}-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 {beta}-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 {beta}-like cells by a small molecule FoxO1 inhibitor, paving the way for clinical applications. One Sentence SummaryOrally available small molecule FoxO1 inhibitor phenocopied genetic FoxO1 ablation in generating gut {beta}-like cells