| First Author | Kitamoto T | Year | 2022 |
| Journal | Mol Metab | Volume | 66 |
| Pages | 101624 | PubMed ID | 36341906 |
| Mgi Jnum | J:341737 | Mgi Id | MGI:7386151 |
| Doi | 10.1016/j.molmet.2022.101624 | Citation | Kitamoto T, et al. (2022) Chemical induction of gut beta-like-cells by combined FoxO1/Notch inhibition as a glucose-lowering treatment for diabetes. Mol Metab 66:101624 |
| abstractText | OBJECTIVE: 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. METHODS: We used Ngn3-or Villin-driven FoxO1 ablation to capture the distinctive developmental effects of FoxO1 on EEC pool. We combined FoxO1 ablation with Notch inhibition to enhance the expansion of EEC pool. We tested the ability of an orally available small molecule of FoxO1 inhibitor, Cpd10, to phenocopy genetic ablation of FoxO1. We evaluated the therapeutic impact of genetic ablation or chemical inhibition of FoxO1 on insulin-deficient diabetes in Ins2(Akita/+) mice. RESULTS: Pan-intestinal epithelial FoxO1 ablation expanded the EEC pool, induced beta-like cells, and improved glucose tolerance in Ins2(Akita/+) mice. This genetic effect was phenocopied by Cpd10. Cpd10 induced beta-like cells that released insulin in response to glucose in gut organoids, and this effect was enhanced by the Notch inhibitor, DBZ. In Ins2(Akita/+) mice, a five-day course of either Cpd10 or DBZ induced intestinal insulin-immunoreactive beta-like cells, lowered glycemia, and increased plasma insulin levels without apparent adverse effects. CONCLUSION: 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. |
