Metformin strongly affects transcriptome of peripheral blood cells in healthy individuals

• Published in: PloS one Vol. 14; no. 11; p. e0224835
• Main Authors: Briviba, Monta, Silamikelis, Ivars, Kalnina, Ineta, Ansone, Laura, Rovite, Vita, Elbere, Ilze, Radovica-Spalvina, Ilze, Fridmanis, Davids, Aladyeva, Jekaterina, Konrade, Ilze, Pirags, Valdis, Klovins, Janis
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08.11.2019; Public Library of Science (PLoS)
• Subjects: Adult; Analysis; Antidiabetics; Beta2 protein; Biological markers; Biology and life sciences; Biomarkers; Biomedical research; Blood; Blood cells; Blood Cells - drug effects; Blood Cells - metabolism; Cancer; Carbon tetrachloride; Cell adhesion & migration; Cell cycle; Cholesterol; Clinical Trials as Topic; Computational Biology - methods; CXCR4 protein; Cytokines; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes therapy; DNA methylation; DQA1 protein; Drug dosages; Feces - chemistry; Female; Gene expression; Gene Expression Profiling; Gene Expression Regulation - drug effects; Gene regulation; Gene sequencing; Genes; Genomes; Health aspects; Healthy Volunteers; Hepatocyte nuclear factor 4; High-Throughput Nucleotide Sequencing; Histocompatibility antigen HLA; HLA antigens; Homeostasis; Humans; Immune response; Immune system; Immunoglobulin A; Insulin; Intestine; Kinases; Liver; Male; Medicine and Health Sciences; Metabolism; Metformin; Metformin - pharmacology; Middle Aged; Molecular Sequence Annotation; Next-generation sequencing; Peripheral blood; Receptors, Fc; Research and analysis methods; Ribonucleic acid; RNA; Studies; Target recognition; Transcription; Transcriptome; Type 2 diabetes; Young Adult; Latvia
• DOI: 10.1371/journal.pone.0224835
• ISSN: 1932-6203

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.