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Trimethylamine N-oxide impairs β-cell function and glucose tolerance

Author

Listed:
  • Lijuan Kong

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Qijin Zhao

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Xiaojing Jiang

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Jinping Hu

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Qian Jiang

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Li Sheng

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Xiaohong Peng

    (Peking University
    Peking University)

  • Shusen Wang

    (Tianjin First Central Hospital)

  • Yibing Chen

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Yanjun Wan

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Shaocong Hou

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Xingfeng Liu

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Chunxiao Ma

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Yan Li

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Li Quan

    (Peking University)

  • Liangyi Chen

    (Peking University
    Peking University)

  • Bing Cui

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Pingping Li

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

Abstract

β-Cell dysfunction and β-cell loss are hallmarks of type 2 diabetes (T2D). Here, we found that trimethylamine N-oxide (TMAO) at a similar concentration to that found in diabetes could directly decrease glucose-stimulated insulin secretion (GSIS) in MIN6 cells and primary islets from mice or humans. Elevation of TMAO levels impairs GSIS, β-cell proportion, and glucose tolerance in male C57BL/6 J mice. TMAO inhibits calcium transients through NLRP3 inflammasome-related cytokines and induced Serca2 loss, and a Serca2 agonist reversed the effect of TMAO on β-cell function in vitro and in vivo. Additionally, long-term TMAO exposure promotes β-cell ER stress, dedifferentiation, and apoptosis and inhibits β-cell transcriptional identity. Inhibition of TMAO production improves β-cell GSIS, β-cell proportion, and glucose tolerance in both male db/db and choline diet-fed mice. These observations identify a role for TMAO in β-cell dysfunction and maintenance, and inhibition of TMAO could be an approach for the treatment of T2D.

Suggested Citation

  • Lijuan Kong & Qijin Zhao & Xiaojing Jiang & Jinping Hu & Qian Jiang & Li Sheng & Xiaohong Peng & Shusen Wang & Yibing Chen & Yanjun Wan & Shaocong Hou & Xingfeng Liu & Chunxiao Ma & Yan Li & Li Quan &, 2024. "Trimethylamine N-oxide impairs β-cell function and glucose tolerance," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46829-0
    DOI: 10.1038/s41467-024-46829-0
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    References listed on IDEAS

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