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

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, Liangyi Chen, Bing Cui and Pingping Li ()
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Lijuan Kong: Chinese Academy of Medical Sciences and Peking Union Medical College
Qijin Zhao: Chinese Academy of Medical Sciences and Peking Union Medical College
Xiaojing Jiang: Chinese Academy of Medical Sciences and Peking Union Medical College
Jinping Hu: Chinese Academy of Medical Sciences and Peking Union Medical College
Qian Jiang: Chinese Academy of Medical Sciences and Peking Union Medical College
Li Sheng: Chinese Academy of Medical Sciences and Peking Union Medical College
Xiaohong Peng: Peking University
Shusen Wang: Tianjin First Central Hospital
Yibing Chen: Chinese Academy of Medical Sciences and Peking Union Medical College
Yanjun Wan: Chinese Academy of Medical Sciences and Peking Union Medical College
Shaocong Hou: Chinese Academy of Medical Sciences and Peking Union Medical College
Xingfeng Liu: Chinese Academy of Medical Sciences and Peking Union Medical College
Chunxiao Ma: Chinese Academy of Medical Sciences and Peking Union Medical College
Yan Li: Chinese Academy of Medical Sciences and Peking Union Medical College
Li Quan: Peking University
Liangyi Chen: Peking University
Bing Cui: Chinese Academy of Medical Sciences and Peking Union Medical College
Pingping Li: Chinese Academy of Medical Sciences and Peking Union Medical College

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46829-0

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