ABSTRACT
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.
Highlights
Gut FoxO1 ablation enriched enteroendocrine cells (EECs) in mice small intestine
Gut FoxO1 ablation can reversed hyperglycemia in diabetic Akita mice
FoxO1 ablation in Neurog3 cells more efficiently altered EEC lineage than in pan-intestinal epithelial cells
Dual FoxO1/Notch inhibition synergistically boosted EEC lineage and β-like-cells
Orally available small molecule FoxO1 inhibitor phenocopied genetic FoxO1 ablation in generating gut β-like cells
Competing Interest Statement
. D.A. is founder, director, chair of the advisory board, and holds an equity interest in Forkhead Biotherapeutics, Inc. Y.-K.L. and S.B. are employees of Forkhead Biotherapeutics, Inc. Hua V. Lin is a former employee of Forkhead Biotherapeutics. T.K., D.A., H.V.L., Y.-K.L., and S.B. are inventors on a patent application describing some the findings.