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

Nature genetics | Apr 29, 2012

http://www.ncbi.nlm.nih.gov/pubmed/22406641

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 RIS Download

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

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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

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