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

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.

Pubmed ID: 22406641

Authors

  • Talchai C
  • Xuan S
  • Kitamura T
  • DePinho RA
  • Accili D

Journal

Nature genetics

Publication Data

April 29, 2012

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK58282
  • Agency: NIDDK NIH HHS, Id: DK63608
  • Agency: NIDDK NIH HHS, Id: DK64819
  • Agency: NIDDK NIH HHS, Id: P30 DK063608
  • Agency: NIDDK NIH HHS, Id: P30 DK063608-10
  • Agency: NIDDK NIH HHS, Id: R01 DK057539
  • Agency: NIDDK NIH HHS, Id: R01 DK057539-12
  • Agency: NIDDK NIH HHS, Id: R01 DK064819
  • Agency: NIDDK NIH HHS, Id: R01 DK064819-10
  • Agency: NIDDK NIH HHS, Id: R37 DK058282
  • Agency: NIDDK NIH HHS, Id: R37 DK058282-13

Mesh Terms

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