Diabetes treatment by conversion of gut epithelial cells to insulin‐producing cells

Abstract Insulin‐deficient (type 1) diabetes is treated by providing insulin to maintain euglycemia. The current standard of care is a quasi‐closed loop integrating automated insulin delivery with a continuous glucose monitoring sensor. Cell replacement technologies are advancing as an alternative treatment and have been tested as surrogates to cadaveric islets in transplants. In addition, immunomodulatory treatments to delay the onset of type 1 diabetes in high‐risk (stage 2) individuals have gained regulatory approval. We have pioneered a cell conversion approach to restore insulin production through pharmacological conversion of intestinal epithelial cells into insulin‐producing cells. We have advanced this approach along a translational trajectory through the discovery of small molecule forkhead box protein O1 inhibitors. When administered to different rodent models of insulin‐deficient diabetes, these inhibitors have resulted in robust glucose‐lowering responses and generation of insulin‐producing cells in the gut epithelium. We review past work and delineate a path to human clinical trials.