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

ABSTRACT:

Objectives

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 β-like cells by targeted inhibition of FOXO1. We have previously 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.

Methods

We profiled two novel FOXO1 inhibitors in reporter gene assays, and hepatocyte gene expression studies, and in vivo pyruvate tolerance test (PTT) for their activity and specificity. We evaluated their glucose-lowering effect in mice rendered insulin-deficient by ad

SUBMITTER: Lee YK 

PROVIDER: S-EPMC9676376 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature