Biology subjects

Belvedere, S.

Publications and source records attributed to Belvedere, S..

3 recordsLinked to original sources

bioRxiv2022

Single-agent Foxo1 inhibition normalizes glycemia and induces gut β-like cells in streptozotocin-diabetic mice

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 {beta}-like cells by targeted inhibition of Foxo1. We have 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. In the present study, we provide evidence that two novel Foxo1 inhibitors, FBT432 and FBT374 have glucose-lowering and gut {beta}-like cell-inducing properties in mice rendered insulin-deficient by administration of streptozotocin. FBT432 is also highly effective in combination with a Notch inhibitor in this model. The data add to a growing body of evidence suggesting that Foxo1 inhibition be pursued as an alternative treatment to insulin administration in diabetes.

pharmacology and toxicology↗

bioRxiv2022

Triple Notch/Tgfβ/FoxO1 blockade converts multiple intestinal sub-lineages into β-like cells and lowers glycemia in diabetic animals

Insulin is the essential treatment of Type 1 (T1D) and is often used in Type 2 Diabetes. For nearly five decades, efforts have been focused on replenishing {beta}-cells in T1D patients as a more durable treatment. Gut endocrine cells can be converted into insulin-producing cells, 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, in addition to enteroendocrine cells. Accordingly, lineage tracing experiments show that, besides enterochromaffin cells, the Paneth/goblet lineage can undergo conversion to the insulin lineage upon genetic or pharmacologic Foxo1 ablation in mice. We leveraged these data to design a screening platform in organoids to accurately quantitate {beta}-like cell reprogramming and fine-tune a combination treatment to increase the efficiency of the conversion process by expanding the intestinal secretory lineage. We identified a triple blockade of FoxO1, Notch, and Tgf{beta} that, when tested in insulin-deficient diabetic animals resulted in a near-normalization of glucose levels, associated with the appearance of gut insulin-producing cells. The findings illustrate a therapeutic approach to replace insulin treatment in diabetes.

cell biology↗

bioRxiv2021

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

Lifelong insulin replacement remains the mainstay of type 1 diabetes treatment. Genetic FoxO1 ablation promotes enteroendocrine cell (EECs) conversion into glucose-responsive {beta}-like cells. Here, we tested whether chemical FoxO1 inhibitors can generate {beta}-like gut cells. Pan-intestinal epithelial FoxO1 ablation expanded the EEC pool, induced {beta}-like cells, and improved glucose tolerance in Ins2Akita/+ mice. This genetic effect was phenocopied by small molecule FoxO1 inhibitor, Cpd10. Cpd10 induced {beta}-like cells that released insulin in response to glucose in mouse gut organoids, and this effect was strengthened by the Notch inhibitor, DBZ. In Ins2Akita/+ mice, a five-day course of either Cpd10 or DBZ induced insulin-immunoreactive {beta}-like cells in the gut, lowered glycemia, and increased plasma insulin levels without apparent adverse effects. These results provide proof of principle of gut cell conversion into {beta}-like cells by a small molecule FoxO1 inhibitor, paving the way for clinical applications. One Sentence SummaryOrally available small molecule FoxO1 inhibitor phenocopied genetic FoxO1 ablation in generating gut {beta}-like cells

developmental biology↗