| First Author | Du W | Year | 2022 |
| Journal | J Clin Invest | Volume | 132 |
| Issue | 24 | PubMed ID | 36282594 |
| Mgi Jnum | J:333472 | Mgi Id | MGI:7412731 |
| Doi | 10.1172/JCI162720 | Citation | Du W, et al. (2022) Pharmacological conversion of gut epithelial cells into insulin-producing cells lowers glycemia in diabetic animals. J Clin Invest 132(24) |
| abstractText | As a highly regenerative organ, the intestine is a promising source for cellular reprogramming for replacing lost pancreatic beta cells in diabetes. Gut enterochromaffin cells can be converted to insulin-producing cells by forkhead box O1 (FoxO1) ablation, but their numbers are limited. In this study, we report that insulin-immunoreactive cells with Paneth/goblet cell features are present in human fetal intestine. Accordingly, lineage-tracing experiments show that, upon genetic or pharmacologic FoxO1 ablation, the Paneth/goblet lineage can also undergo conversion to the insulin lineage. We designed a screening platform in gut organoids to accurately quantitate beta-like cell reprogramming and fine-tune a combination treatment to increase the efficiency of the conversion process in mice and human adult intestinal organoids. We identified a triple blockade of FOXO1, Notch, and TGF-beta that, when tested in insulin-deficient streptozotocin (STZ) or NOD diabetic animals, resulted in near normalization of glucose levels, associated with the generation of intestinal insulin-producing cells. The findings illustrate a therapeutic approach for replacing insulin treatment in diabetes. |
