Abstract
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.
Highlights
Metformin is the first-line antidiabetic agent used in pharmacotherapy of type 2 diabetes to improve glucose homeostasis[1]
Differential global gene expression induced by administration of metformin In order to reveal the target genes and pathways affected by metformin, we performed a transcriptome analysis in whole-blood samples of 25 healthy volunteers receiving metformin for one week (Table 1)
Venous blood samples were obtained at three consecutive time-points, hereinafter referred to as M0, M10h (10 hours after the first metformin intake/before the second dose) and M7d in order to observe both, acute and sustained effects of metformin
Summary
Metformin is the first-line antidiabetic agent used in pharmacotherapy of type 2 diabetes to improve glucose homeostasis[1]. Various additional therapeutic benefits beyond its antihyperglycaemic action have been highlighted lately, justifying the pleiotropic effect of the drug. In patients with type 2 diabetes metformin therapy is associated with reduced cardiovascular morbidity[2]. Metformin exposure has a protective role against tumorigenesis in various types of cancers and it is proved to be beneficial in the preventive oncology regardless of the diabetic state[3, 4].
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