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

Talchai C, Xuan S, Kitamura T, DePinho RA, Accili D
Nat Genet. 2012 44 (4): 406-12, S1

PMID: 22406641 · PMCID: PMC3315609 · DOI:10.1038/ng.2215

Restoration of regulated insulin secretion is the ultimate goal of therapy for type 1 diabetes. Here, we show that, unexpectedly, somatic ablation of Foxo1 in Neurog3(+) enteroendocrine progenitor cells gives rise to gut insulin-positive (Ins(+)) cells 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 showed that gut Ins(+) cells arise cell autonomously from Foxo1-deficient cells. Inducible Foxo1 ablation in adult mice also resulted 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.

MeSH Terms (22)

Animals Basic Helix-Loop-Helix Transcription Factors C-Peptide Cell Differentiation Diabetes Mellitus, Experimental Enteroendocrine Cells Forkhead Box Protein O1 Forkhead Transcription Factors Gastrointestinal Tract Glucose Hyperglycemia Insulin Insulin-Secreting Cells Insulin Secretion Mice Mice, Transgenic Nerve Tissue Proteins Neuroendocrine Cells Stem Cells Streptozocin Sulfonylurea Compounds Wnt Signaling Pathway

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