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Significantly altered peripheral blood cell DNA methylation profile as a result of immediate effect of metformin use in healthy individuals
Latvian Biomed Res & Study Ctr, Ratsupites Str 1 K-1, LV-1067 Riga, Latvia.
Latvian Biomed Res & Study Ctr, Ratsupites Str 1 K-1, LV-1067 Riga, Latvia.
Latvian Biomed Res & Study Ctr, Ratsupites Str 1 K-1, LV-1067 Riga, Latvia.
Latvian Biomed Res & Study Ctr, Ratsupites Str 1 K-1, LV-1067 Riga, Latvia.
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2018 (English)In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 10, article id 156Article in journal (Refereed) Published
Abstract [en]

Background: Metformin 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.

Results: Twelve healthy metformin-naive individuals where enrolled in the study. Genome-wide DNA methylation pattern was estimated at baseline, 10h and 7days 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.

Conclusions: Here 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.

Place, publisher, year, edition, pages
2018. Vol. 10, article id 156
Keywords [en]
Metformin, Epigenetics, DNA methylation, White blood cells, Longitudinal study
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-372930DOI: 10.1186/s13148-018-0593-xISI: 000453254200002PubMedID: 30545422OAI: oai:DiVA.org:uu-372930DiVA, id: diva2:1277463
Available from: 2019-01-10 Created: 2019-01-10 Last updated: 2019-03-14Bibliographically approved

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