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bioRxiv · 10.1101/2022.03.26.485929

Single-agent Foxo1 inhibition normalizes glycemia and induces gut β-like cells in streptozotocin-diabetic mice

Lee, Y.-K.·Nie, Y.·Diaz, B.·Sultana, N.·Kitamoto, T.·Du, W.·Leibel, R.·Accili, D.·Belvedere, S.
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Abstract

Insulin treatment remains the sole effective intervention for Type 1 Diabetes. Here, we investigated the therapeutic potential of converting intestinal epithelial cells to insulin-producing, glucose-responsive {beta}-like cells by targeted inhibition of Foxo1. We have shown that this can be achieved by genetic ablation in gut Neurogenin3 progenitors, adenoviral or shRNA-mediated inhibition in human gut organoids, and chemical inhibition in Akita mice, a model of insulin-deficient diabetes. In the present study, we provide evidence that two novel Foxo1 inhibitors, FBT432 and FBT374 have glucose-lowering and gut {beta}-like cell-inducing properties in mice rendered insulin-deficient by administration of streptozotocin. FBT432 is also highly effective in combination with a Notch inhibitor in this model. The data add to a growing body of evidence suggesting that Foxo1 inhibition be pursued as an alternative treatment to insulin administration in diabetes.

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Lee, Y.-K., Nie, Y., Diaz, B., Sultana, N., Kitamoto, T., Du, W., Leibel, R., Accili, D., Belvedere, S.. 2022-03-27. Single-agent Foxo1 inhibition normalizes glycemia and induces gut β-like cells in streptozotocin-diabetic mice. https://doi.org/10.1101/2022.03.26.485929

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