Pharmacological conversion of gut epithelial cells into insulin-producing cells lowers glycemia in diabetic animals.

Citation
Du, W., et al. “Pharmacological Conversion Of Gut Epithelial Cells Into Insulin-Producing Cells Lowers Glycemia In Diabetic Animals.”. The Journal Of Clinical Investigation.
Center Columbia University
Featured
Author Wen Du, Junqiang Wang, Taiyi Kuo, Liheng Wang, Wendy M McKimpson, Jinsook Son, Hitoshi Watanabe, Takumi Kitamoto, Yun-Kyoung Lee, Rémi J Creusot, Lloyd E Ratner, Kasi McCune, Ya-Wen Chen, Brendan H Grubbs, Matthew E Thornton, Jason Fan, Nishat Sultana, Bryan S Diaz, Iyshwarya Balasubramanian, Nan Gao, Sandro Belvedere, Domenico Accili
Keywords beta cells, diabetes, Endocrinology, insulin
Abstract

As a highly regenerative organ, the intestine is a promising source for cellular reprogramming to replace lost pancreatic β-cells in diabetes. Gut enterochromaffin cells can be converted to insulin-producing cells by 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 β-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 TGFβ that, when tested in insulin-deficient 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 to replace insulin treatment in diabetes.

Year of Publication
2022
Journal
The Journal of clinical investigation
Date Published
10/2022
ISSN Number
1558-8238
DOI
10.1172/JCI162720
Alternate Journal
J Clin Invest
PMID
36282594