Trimethylamine N-oxide impairs β-cell function and glucose tolerance
Lijuan Kong, Qijin Zhao, Xiaojing Jiang, Jinping Hu, Qian Jiang, Sheng Li, Xiaohong Peng, Shusen Wang, Yibing Chen, Yanjun Wan, Shaocong Hou, Xingfeng Liu, Chunxiao Ma, Yan Li, Quan Li, Liangyi Chen, Bing Cui, Pingping Li
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.