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

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  • Additional Information
    • Source:
      Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
    • Publication Information:
      Original Publication: [London] : Nature Pub. Group
    • Subject Terms:
      Diabetes Mellitus, Type 2*; Humans ; Male ; Animals ; Mice ; Mice, Inbred C57BL ; Glucose/pharmacology ; Methylamines/pharmacology ; Signal Transduction ; Insulin/pharmacology
    • 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.
      (© 2024. The Author(s).)
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    • Accession Number:
      FLD0K1SJ1A (trimethyloxamine)
      IY9XDZ35W2 (Glucose)
      0 (Methylamines)
      0 (Insulin)
    • Publication Date:
      Date Created: 20240322 Date Completed: 20240325 Latest Revision: 20240325
    • Publication Date:
      20240325
    • Accession Number:
      PMC10957989
    • Accession Number:
      10.1038/s41467-024-46829-0
    • Accession Number:
      38514666