Chemical induction of gut β-like-cells by combined FoxO1/Notch inhibition as a glucose-lowering treatment for diabetes
Objective: Lifelong insulin replacement remains the mainstay of type 1 diabetes treatment. Genetic FoxO1 ablation promotes enteroendocrine cell (EECs) conversion into glucose-responsive β-like cells. Here, we tested whether chemical FoxO1 inhibitors can generate β-like gut cells. Methods: We used Ng...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877822001934 |
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| author | Takumi Kitamoto Yun-Kyoung Lee Nishat Sultana Hitoshi Watanabe Wendy M. McKimpson Wen Du Jason Fan Bryan Diaz Hua V. Lin Rudolph L. Leibel Sandro Belvedere Domenico Accili |
| author_facet | Takumi Kitamoto Yun-Kyoung Lee Nishat Sultana Hitoshi Watanabe Wendy M. McKimpson Wen Du Jason Fan Bryan Diaz Hua V. Lin Rudolph L. Leibel Sandro Belvedere Domenico Accili |
| author_sort | Takumi Kitamoto |
| collection | DOAJ |
| description | Objective: Lifelong insulin replacement remains the mainstay of type 1 diabetes treatment. Genetic FoxO1 ablation promotes enteroendocrine cell (EECs) conversion into glucose-responsive β-like cells. Here, we tested whether chemical FoxO1 inhibitors can generate β-like gut cells. Methods: We used Ngn3-or Villin-driven FoxO1 ablation to capture the distinctive developmental effects of FoxO1 on EEC pool. We combined FoxO1 ablation with Notch inhibition to enhance the expansion of EEC pool. We tested the ability of an orally available small molecule of FoxO1 inhibitor, Cpd10, to phenocopy genetic ablation of FoxO1. We evaluated the therapeutic impact of genetic ablation or chemical inhibition of FoxO1 on insulin-deficient diabetes in Ins2Akita/+ mice. Results: Pan-intestinal epithelial FoxO1 ablation expanded the EEC pool, induced β-like cells, and improved glucose tolerance in Ins2Akita/+ mice. This genetic effect was phenocopied by Cpd10. Cpd10 induced β-like cells that released insulin in response to glucose in gut organoids, and this effect was enhanced by the Notch inhibitor, DBZ. In Ins2Akita/+ mice, a five-day course of either Cpd10 or DBZ induced intestinal insulin-immunoreactive β-like cells, lowered glycemia, and increased plasma insulin levels without apparent adverse effects. Conclusion: These results provide proof of principle of gut cell conversion into β-like cells by a small molecule FoxO1 inhibitor, paving the way for clinical applications. |
| first_indexed | 2024-04-11T13:06:32Z |
| format | Article |
| id | doaj.art-df93c47e5c174cc68dabf3af76c69142 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-04-11T13:06:32Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-df93c47e5c174cc68dabf3af76c691422022-12-22T04:22:45ZengElsevierMolecular Metabolism2212-87782022-12-0166101624Chemical induction of gut β-like-cells by combined FoxO1/Notch inhibition as a glucose-lowering treatment for diabetesTakumi Kitamoto0Yun-Kyoung Lee1Nishat Sultana2Hitoshi Watanabe3Wendy M. McKimpson4Wen Du5Jason Fan6Bryan Diaz7Hua V. Lin8Rudolph L. Leibel9Sandro Belvedere10Domenico Accili11Department of Medicine and Columbia University, New York, NY 10032, USA; Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA; Chiba University Graduate School of Medicine, Chiba, Japan, 2608670; Corresponding author. Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.Forkhead BioTherapeutics, Inc., New York, NY, USADepartment of Pediatrics Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USADepartment of Medicine and Columbia University, New York, NY 10032, USA; Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USADepartment of Medicine and Columbia University, New York, NY 10032, USA; Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USADepartment of Medicine and Columbia University, New York, NY 10032, USA; Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USADepartment of Ophthalmology, Bascom Palmer Eye Institute, University of Miami, Miami, FL, 33146, USADepartment of Pediatrics Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USABioFront Therapeutics, Beijing, ChinaDepartment of Pediatrics Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USAForkhead BioTherapeutics, Inc., New York, NY, USADepartment of Medicine and Columbia University, New York, NY 10032, USA; Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USAObjective: Lifelong insulin replacement remains the mainstay of type 1 diabetes treatment. Genetic FoxO1 ablation promotes enteroendocrine cell (EECs) conversion into glucose-responsive β-like cells. Here, we tested whether chemical FoxO1 inhibitors can generate β-like gut cells. Methods: We used Ngn3-or Villin-driven FoxO1 ablation to capture the distinctive developmental effects of FoxO1 on EEC pool. We combined FoxO1 ablation with Notch inhibition to enhance the expansion of EEC pool. We tested the ability of an orally available small molecule of FoxO1 inhibitor, Cpd10, to phenocopy genetic ablation of FoxO1. We evaluated the therapeutic impact of genetic ablation or chemical inhibition of FoxO1 on insulin-deficient diabetes in Ins2Akita/+ mice. Results: Pan-intestinal epithelial FoxO1 ablation expanded the EEC pool, induced β-like cells, and improved glucose tolerance in Ins2Akita/+ mice. This genetic effect was phenocopied by Cpd10. Cpd10 induced β-like cells that released insulin in response to glucose in gut organoids, and this effect was enhanced by the Notch inhibitor, DBZ. In Ins2Akita/+ mice, a five-day course of either Cpd10 or DBZ induced intestinal insulin-immunoreactive β-like cells, lowered glycemia, and increased plasma insulin levels without apparent adverse effects. Conclusion: These results provide proof of principle of gut cell conversion into β-like cells by a small molecule FoxO1 inhibitor, paving the way for clinical applications.http://www.sciencedirect.com/science/article/pii/S2212877822001934DiabetesInsulinβ cell replacementFOXO1FoxO1 inhibitorNotch inhibition |
| spellingShingle | Takumi Kitamoto Yun-Kyoung Lee Nishat Sultana Hitoshi Watanabe Wendy M. McKimpson Wen Du Jason Fan Bryan Diaz Hua V. Lin Rudolph L. Leibel Sandro Belvedere Domenico Accili Chemical induction of gut β-like-cells by combined FoxO1/Notch inhibition as a glucose-lowering treatment for diabetes Molecular Metabolism Diabetes Insulin β cell replacement FOXO1 FoxO1 inhibitor Notch inhibition |
| title | Chemical induction of gut β-like-cells by combined FoxO1/Notch inhibition as a glucose-lowering treatment for diabetes |
| title_full | Chemical induction of gut β-like-cells by combined FoxO1/Notch inhibition as a glucose-lowering treatment for diabetes |
| title_fullStr | Chemical induction of gut β-like-cells by combined FoxO1/Notch inhibition as a glucose-lowering treatment for diabetes |
| title_full_unstemmed | Chemical induction of gut β-like-cells by combined FoxO1/Notch inhibition as a glucose-lowering treatment for diabetes |
| title_short | Chemical induction of gut β-like-cells by combined FoxO1/Notch inhibition as a glucose-lowering treatment for diabetes |
| title_sort | chemical induction of gut β like cells by combined foxo1 notch inhibition as a glucose lowering treatment for diabetes |
| topic | Diabetes Insulin β cell replacement FOXO1 FoxO1 inhibitor Notch inhibition |
| url | http://www.sciencedirect.com/science/article/pii/S2212877822001934 |
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