Similarities and differences in the intestinal actions of metformin and imeglimin

Aims Imeglimin is a novel antidiabetic drug that shares structural similarity with metformin. While the intestinal effects of metformin have attracted widespread attention, those of imeglimin remain underexplored. Materials and methods C57BL/6J mice were treated with metformin or imeglimin for RNA sequencing of intestinal tissue. Gut microbiota composition was evaluated in KK‐A y mice by 16S rRNA sequencing of faecal samples. To assess direct effects on the human microbiome, a gut simulator was used with faecal samples from healthy and diabetic individuals. Intestinal glucose dynamics were assessed in C57BL/6J mice following administration of [ 18 F]fluorodeoxyglucose, with subsequent analysis of tissue distribution. Results Bulk RNA‐sequencing of colonic tissue revealed that both drugs induced similar patterns of gene expression changes, including a prominent upregulation of Gdf15. However, single‐cell RNA‐sequencing uncovered distinct effects of the two drugs, with metformin having a pronounced impact on the functional properties of enterocytes and imeglimin increasing the proportion of IgA‐producing plasma cells. Metformin reduced gut microbial diversity and induced substantial changes in microbial composition, whereas imeglimin exerted less pronounced effects. Gut simulator analysis with human faecal samples showed that both drugs directly altered gut microbial populations but in different ways. Finally, metformin promoted glucose excretion into the intestinal lumen, whereas imeglimin had a minimal effect on this process. Conclusions In conclusion, although metformin and imeglimin exerted similar effects on gene expression in the colon at the whole‐tissue level, they showed distinct cell type–specific actions, and they differed in their influence on gut microbiota and intestinal glucose dynamics.