Metformin strongly affects transcriptome of peripheral blood cells in healthy individuals

摘要

Metformin is a commonly used antihyperglycaemic agent for the treatment of type 2 diabetes mellitus. Nevertheless, the exact mechanisms of action, underlying the various therapeutic effects of metformin, remain elusive. The goal of this study was to evaluate the alterations in longitudinal whole-blood transcriptome profiles of healthy individuals after a one-week metformin intervention in order to identify the novel molecular targets and further prompt the discovery of predictive biomarkers of metformin response. Next generation sequencing-based transcriptome analysis revealed metformin-induced differential expression of genes involved in intestinal immune network for IgA production and cytokine-cytokine receptor interaction pathways. Significantly elevated faecal sIgA levels during administration of metformin, and its correlation with the expression of genes associated with immune response ( CXCR4 , HLA-DQA1 , MAP3K14 , TNFRSF21 , CCL4 , ACVR1B , PF4 , EPOR , CXCL8 ) supports a novel hypothesis of strong association between metformin and intestinal immune system, and for the first time provide evidence for altered RNA expression as a contributing mechanism of metformin’s action. In addition to universal effects, 4 clusters of functionally related genes with a subject-specific differential expression were distinguished, including genes relevant to insulin production ( HNF1B , HNF1A , HNF4A , GCK , INS , NEUROD1 , PAX4 , PDX1 , ABCC8 , KCNJ11 ) and cholesterol homeostasis ( APOB , LDLR , PCSK9 ). This inter-individual variation of the metformin effect on the transcriptional regulation goes in line with well-known variability of the therapeutic response to the drug.