Lifelong insulin replacement remains the mainstay of type1 diabetes treatment. Three potentially complementary approaches are vying to replace it: autonomous insulin delivery devices integrated with real-time glucose measurements, implants of stem cell-derived b-like-cells, and immunotherapies. We have championed the alternative approach of converting enteroendocrine cells (EECs) into glucose-responsive β-like cells. We have shown that this can be achieved in mice and human gut organoids by genetic ablation of transcription factor FoxO1. To translate these observations into a clinical approach, we have pursued the generation of small molecule FoxO1 inhibitors to evaluate their ability to bring about a similar effect in vivo. We have developed different small molecule FoxO1 inhibitors (FBT) that reduce FoxO1 activity by up to 70% and show no significant off-target effects. We have tested FBT compounds alone and in combination with different Notch and TGFb1 inhibitors for their effect on EEC cell conversion in three different mouse models of insulin-deficient diabetes: NOD, STZ, and Akita (Ins2 mutation). Combination treatment had the primary goal of expanding the EEC pool and increase the number of cells amenable to conversion. When orally administered to mice, FBT promoted the formation of insulin- and C-peptide-positive cells in the gut of mice within 48 hours. On average, 1 insulin-immunoreactive cell was generated in each intestinal villus. Treatment with FBT, alone or in combination with a Notch inhibitor, or with a Notch and TGFb1 inhibitor, lowered glycemia by between 150 and 400 mg/dl in the different diabetic models without toxic effects. Immunohistochemistry, fluorescence cell sorting, and single cell RNA sequencing analyses demonstrated the presence of β-like cells. The present findings provide proof of principle that conversion of gut cells to β-like cells can be achieved by oral delivery of a small molecule FoxO1 inhibitor, paving the way for clinical application.