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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: Pan-intestinal epithelial FoxO1 ablation expanded the EEC pool, induced β-like cells, and improved glucose tolerance in Ins2 Akita/+ mice. This genetic effect was phenocopied by Cpd10. Cpd10 induced β-like cells that released insulin in response to glucose in gut organoids, and this effect was enhanced by the Notch inhibitor, DBZ. In Ins2 Akita/+ mice, a five-day course of either Cpd10 or DBZ induced intestinal insulin-immunoreactive β-like cells, lowered glycemia, and increased plasma insulin levels without apparent adverse effects., Conclusion: These results provide proof of principle of gut cell conversion into β-like cells by a small molecule FoxO1 inhibitor, paving the way for clinical applications., (Copyright © 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Objective: Forkhead box protein O1 (FOXO1) plays a key role in regulating hepatic glucose production, but investigations of FOXO1 inhibition as a potential therapeutic approach have been hampered by a lack of selective chemical inhibitors. By profiling structurally diverse FOXO1 inhibitors, the current study validates FOXO1 as a viable target for the treatment of diabetes., Methods: Using reporter gene assays, hepatocyte gene expression studies, and in vivo studies in mice, we profiled our leading tool compound 10 and a previously characterized FOXO1 inhibitor, AS1842856 (AS)., Results: We show that AS has significant FOXO1-independent effects, as demonstrated by testing in FOXO1-deficient cell lines and animals, while compound 10 is highly selective for FOXO1 both in vitro and in vivo and fails to elicit any effect in genetic models of FOXO1 ablation. Chronic administration of compound 10 improved insulin sensitivity and glucose control in db/db mice without causing weight gain. Furthermore, chronic compound 10 treatment combined with FGF21 led to synergistic glucose lowering in lean, streptozotocin-induced diabetic mice., Conclusions: We show that the widely used AS compound has substantial off-target activities and that compound 10 is a superior tool molecule for the investigation of FOXO1 function. In addition, we provide preclinical evidence that selective FOXO1 inhibition has potential therapeutic benefits for diabetes as a monotherapy or in combination with FGF21., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Objective: GPR142 agonists are being pursued as novel diabetes therapies by virtue of their insulin secretagogue effects. But it is undetermined whether GPR142's functions in pancreatic islets are limited to regulating insulin secretion. The current study expands research on its action., Methods and Results: We demonstrated by in situ hybridization and immunostaining that GPR142 is expressed not only in β cells but also in a subset of α cells. Stimulation of GPR142 by a selective agonist increased glucagon secretion in both human and mouse islets. More importantly, the GPR142 agonist also potentiated glucagon-like peptide-1 (GLP-1) production and its release from islets through a mechanism that involves upregulation of prohormone convertase 1/3 expression. Strikingly, stimulation of insulin secretion and increase in insulin content via GPR142 engagement requires intact GLP-1 receptor signaling. Furthermore, GPR142 agonist increased β cell proliferation and protected both mouse and human islets against stress-induced apoptosis., Conclusions: Collectively, we provide here evidence that local GLP-1 release from α cells defines GPR142's beneficial effects on improving β cell function and mass, and we propose that GPR142 agonism may have translatable and durable efficacy for the treatment of type 2 diabetes., (Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.)