Generation of functional insulin-producing cells in the gut by Foxo1 ablation

Abstract

Restoration of regulated insulin secretion is the ultimate goal of type 1 diabetes therapy. Here we show that, surprisingly, somatic ablation of Foxo1 in Neurog3+ enteroendocrine progenitor cells gives rise to gut insulin-positive cells (Ins+) that express markers of mature β-cells, and secrete bioactive insulin as well as C-peptide in response to glucose and sulfonylureas. Lineage tracing experiments show that gut Ins+ cells arise cell-autonomously from Foxo1-deficient cells. Inducible Foxo1 ablation in adult mice also results in the generation of gut Ins+ cells. Following ablation by the β-cell toxin, streptozotocin, gut Ins+ cells regenerate and produce insulin, reversing hyperglycemia in mice. The data indicate that Neurog3+ enteroendocrine progenitors require active Foxo1 to prevent differentiation into Ins+ cells. Foxo1 ablation in gut epithelium may provide an approach to restore insulin production in type 1 diabetes.

FOXOs attenuate bone formation by suppressing Wnt signaling

“…This effect most likely resulted from unleashing β-catenin/ TCF activity and is in agreement with evidence that β-catenin promotes the proliferation of Osx1-expressing cells that reside within the periosteal envelope by stimulating cyclin D1 (8,45). Similar to our findings in the Foxo1,-3,-4-deficient mice, deletion of Foxo1 in enteroendocrine progenitor cells increases proliferation and the expression of several Wnt targets, including cyclin D1 (46).…”

Advances in β cell replacement and regeneration strategies for treating diabetes

“…These reprogrammed cells exhibit ultrastructural features of β cells, are glucose-responsive, and are able to ameliorate hyperglycemia in diabetic mice. Similarly, ablation of the transcription factor FOXO1 in endocrine progenitors of the intestine results in the generation of insulin-expressing cells that are able to reverse hyperglycemia in mice (36). This finding has been reproduced in human gut organoids (23), suggesting that FOXO1 inhibition in gut organoids could offer a source of insulin-producing cells to treat human diabetes.…”

Vitamin A Deficiency Causes Hyperglycemia and Loss of Pancreatic β-Cell Mass

“…We used a monoclonal antibody to Ngn3 that can detect murine Ngn3-positive progenitors in models of pancreatic injury (44). Using a double immunofluorescence approach with antibodies against C-peptide and Ngn3, we were unable to detect endogenous Ngn3-positive areas in our analysis of more than 100 pancreatic endocrine cells, exocrine cells, and ductal fields in all of the dietary VA experimental groups (Fig.…”