Metformin strongly affects transcriptome of peripheral blood cells in healthy individuals
Autoři:
Monta Ustinova aff001; Ivars Silamikelis aff001; Ineta Kalnina aff001; Laura Ansone aff001; Vita Rovite aff001; Ilze Elbere aff001; Ilze Radovica-Spalvina aff001; Davids Fridmanis aff001; Jekaterina Aladyeva aff001; Ilze Konrade aff002; Valdis Pirags aff001; Janis Klovins aff001
Působiště autorů:
Latvian Biomedical Research and Study Centre, Riga, Latvia
aff001; Riga Stradins University, Riga, Latvia
aff002
Vyšlo v časopise:
PLoS ONE 14(11)
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pone.0224835
Souhrn
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.
Klíčová slova:
CD coreceptors – Gastrointestinal tract – Gene expression – Gene ontologies – Immune response – Insulin – RNA sequencing – Transcriptome analysis
Zdroje
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