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

• Published in: bioRxiv
• Main Authors: Kitamoto, Takumi, Lee, Yun-Kyoung, Mckimpson, Wendy M, Watanabe, Hitoshi, Sultana, Nishat, Du, Wen, Fan, Jason, Diaz, Bryan, Lin, Hua V, Leibel, Rudolph L, Belvedere, Sandro, Accili, Domenico
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 07.12.2021
• Subjects: Ablation; Blood glucose; Diabetes; Diabetes mellitus (insulin dependent); Digestive system; Forkhead protein; FOXO1 protein; Gastrointestinal tract; Glucose; Glucose tolerance; Insulin; Organoids; Patent applications
• DOI: 10.1101/2021.12.07.471572

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. 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.