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

Nature Genetics volume 44, pages 406–412 (2012)Cite this article

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Abstract

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.

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Figure 1: Foxo1 ablation in enteroendocrine progenitors expands the pool of Neurog3+ cells.
Figure 2: Gut insulin-producing cells in NKO mice.
Figure 3: Insulin secretion and bioactivity.
Figure 4: Regeneration of gut Ins+ cells following STZ-mediated ablation.
Figure 5: Marker analysis of gut Ins+ cells.
Figure 6: Lineage tracing of Ins+ cells and Aes expression.

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Acknowledgements

We thank A. Efstratiadis (Biomedical Research Foundation, Academy of Athens, Athens, Greece) for Ins2-Gfp knock-in mice and A. Leiter (University of Massachusetts) for Neurog3-Cre mice. We thank L.S., J.Y.K.-M. and T.M. for advice and reagents and Q.X. for technical support. We also thank members of the Accili laboratory for insightful discussion and critical reading of the manuscript. This work was supported by grants from the US National Institutes of Health (DK58282 and DK64819), the Columbia University Diabetes Research Center (DK63608), the Druckenmiller Fellowship of the New York Stem Cell Foundation, the Brehm Coalition and the Russell Berrie Foundation.

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Authors and Affiliations

  1. Naomi Berrie Diabetes Center, Columbia University Medical Center, New York, New York, USA

    Chutima Talchai & Domenico Accili

  2. Department of Medicine, College of Physicians & Surgeons of Columbia University, New York, New York, USA

    Chutima Talchai & Domenico Accili

  3. Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand

    Chutima Talchai

  4. Department of Genetics and Development, College of Physicians & Surgeons of Columbia University, New York, New York, USA

    Shouhong Xuan

  5. Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan

    Tadahiro Kitamura

  6. Department of Cancer Biology, University of Texas MD Anderson Cancer Centerl, Houston, Texas, USA

    Ronald A DePinho

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Contributions

C.T. generated mice, designed and performed experiments and wrote the manuscript. S.X. generated mice and designed experiments. T.K. generated mice and performed immunohistochemistry. R.A.D. and D.A. designed experiments and wrote the manuscript.

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Correspondence to Domenico Accili.

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Talchai, C., Xuan, S., Kitamura, T. et al. Generation of functional insulin-producing cells in the gut by Foxo1 ablation. Nat Genet 44, 406–412 (2012). https://doi.org/10.1038/ng.2215

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