Single-agent FOXO1 inhibition normalizes glycemia and induces gut β-like cells in streptozotocin-diabetic mice

•We describe two novel, orally bioavailable, specific, and potent FOXO1 inhibitors.•The inhibitors generate insulin-immunoreactive intestinal cells.•FBT432 in combination with NOTCH inhibitor, lowers glucose in insulin-deficient mice.•FBT347 as a single agent normalizes glycemia in streptozotocin-induced diabetic mice.•Pharmacological inhibition of FOXO1 can be the cornerstone of insulin replacement treatments.