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

Nature Communications, ISSN: 2041-1723, Vol: 15, Issue: 1, Page: 2526
2024
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Introduction The incidence of metabolic syndrome and diabetes has been steadily increasing over the years, with a notable trend of affecting younger individuals.1 As diabetes

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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.

Bibliographic Details

Kong, Lijuan; Zhao, Qijin; Jiang, Xiaojing; Hu, Jinping; Jiang, Qian; Sheng, Li; Peng, Xiaohong; Wang, Shusen; Chen, Yibing; Wan, Yanjun; Hou, Shaocong; Liu, Xingfeng; Ma, Chunxiao; Li, Yan; Quan, Li; Chen, Liangyi; Cui, Bing; Li, Pingping

Springer Science and Business Media LLC

Chemistry; Biochemistry, Genetics and Molecular Biology; Physics and Astronomy

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