Chemical induction of gut β-like-cells by combined FoxO1/Notch inhibition as a glucose-lowering treatment for diabetes.

ABSTRACT:

Objective

Lifelong insulin replacement remains the mainstay of type 1 diabetes treatment. Genetic FoxO1 ablation promotes enteroendocrine cell (EECs) conversion into glucose-responsive β-like cells. Here, we tested whether chemical FoxO1 inhibitors can generate β-like gut cells.

Methods

We used Ngn3-or Villin-driven FoxO1 ablation to capture the distinctive developmental effects of FoxO1 on EEC pool. We combined FoxO1 ablation with Notch inhibition to enhance the expansion of EEC pool. We tested the ability of an orally available small molecule of FoxO1 inhibitor, Cpd10, to phenocopy genetic ablation of FoxO1. We evaluated the therapeutic impact of genetic ablation or chemical inhibition of FoxO1 on insulin-deficient diabetes in Ins2^Akita/+ mice.

Results

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SUBMITTER: Kitamoto T 

PROVIDER: S-EPMC9664469 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature