Abstract
BackgroundMetformin is a widely prescribed antihyperglycemic agent that has been also associated with multiple therapeutic effects in various diseases, including several types of malignancies. There is growing evidence regarding the contribution of the epigenetic mechanisms in reaching metformin’s therapeutic goals; however, the effect of metformin on human cells in vivo is not comprehensively studied. The aim of our study was to examine metformin-induced alterations of DNA methylation profiles in white blood cells of healthy volunteers, employing a longitudinal study design.ResultsTwelve healthy metformin-naïve individuals where enrolled in the study. Genome-wide DNA methylation pattern was estimated at baseline, 10 h and 7 days after the start of metformin administration. The whole-genome DNA methylation analysis in total revealed 125 differentially methylated CpGs, of which 11 CpGs and their associated genes with the most consistent changes in the DNA methylation profile were selected: POFUT2, CAMKK1, EML3, KIAA1614, UPF1, MUC4, LOC727982, SIX3, ADAM8, SNORD12B, VPS8, and several differentially methylated regions as novel potential epigenetic targets of metformin. The main functions of the majority of top-ranked differentially methylated loci and their representative cell signaling pathways were linked to the well-known metformin therapy targets: regulatory processes of energy homeostasis, inflammatory responses, tumorigenesis, and neurodegenerative diseases.ConclusionsHere we demonstrate for the first time the immediate effect of short-term metformin administration at therapeutic doses on epigenetic regulation in human white blood cells. These findings suggest the DNA methylation process as one of the mechanisms involved in the action of metformin, thereby revealing novel targets and directions of the molecular mechanisms underlying the various beneficial effects of metformin.Trial registrationEU Clinical Trials Register, 2016-001092-74. Registered 23 March 2017, https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-001092-74/LV.
Highlights
Metformin is a widely prescribed antihyperglycemic agent that has been associated with multiple therapeutic effects in various diseases, including several types of malignancies
Characteristics of the study participants We used Illumina Infinium 450k array to evaluate the effect of metformin on DNA methylation in 12 healthy volunteers
The aim of our study was to examine metformin-induced alterations in epigenetic regulation processes by performing genome-wide DNA methylation analysis in human white blood cells followed by estimation of RNA expression levels of identified genes
Summary
Metformin is a widely prescribed antihyperglycemic agent that has been associated with multiple therapeutic effects in various diseases, including several types of malignancies. In the context of possible molecular mechanisms of how metformin induce changes in the methylation profile, a recent study has proved that, in cancer cells, metformin can exert its effects via regulation of the H19/SAHH axis [4]. This has been supported by data showing that metformin promotes global methylation by decreasing S-adenosylhomocysteine (SAH) intracellular levels in various cell types, including non-cancerous [5]. Studies describing other epigenetic effects of metformin have shown its impact on various histone modifications via multiple mechanisms, mostly AMPK dependent, and effect on expression levels of numerous miRNAs through increase in DICER protein levels as well [7]
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