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dc.creatorGarcia-Calzon, S. (Sonia)-
dc.creatorSchrader, S. (Silja)-
dc.creatorPerfilyev, A. (Alexander)-
dc.creatorMartinell, M. (Mats)-
dc.creatorAhlqvist, E. (Emma)-
dc.creatorLing, C. (Charlotte)-
dc.identifier.citationGarcia-Calzon, S. (Sonia); Schrader, S. (Silja); Perfilyev, A. (Alexander); et al. "DNA methylation partially mediates antidiabetic effects of metformin on HbA1c levels in individuals with type 2 diabetes". Diabetes Research and Clinical Practice. 202 (110807), 2023,
dc.description.abstractAims: Despite metformin being used as first-line pharmacological therapy for type 2 diabetes, its underlying mechanisms remain unclear. We aimed to determine whether metformin altered DNA methylation in newlydiagnosed individuals with type 2 diabetes. Methods and Results: We found that metformin therapy is associated with altered methylation of 26 sites in blood from Scandinavian discovery and replication cohorts (FDR < 0.05), using MethylationEPIC arrays. The majority (88%) of these 26 sites were hypermethylated in patients taking metformin for ~ 3 months compared to controls, who had diabetes but had not taken any diabetes medication. Two of these blood-based methylation markers mirrored the epigenetic pattern in muscle and adipose tissue (FDR < 0.05). Four type 2 diabetes-associated SNPs were annotated to genes with differential methylation between metformin cases and controls, e.g., GRB10, RPTOR, SLC22A18AS and TH2LCRR. Methylation correlated with expression in human islets for two of these genes. Three metformin-associated methylation sites (PKNOX2, WDTC1 and MICB) partially mediate effects of metformin on follow-up HbA1c levels. When combining methylation of these three sites into a score, which was used in a causal mediation analysis, methylation was suggested to mediate up to 32% of metformin’s effects on HbA1c. Conclusion: Metformin-associated alterations in DNA methylation partially mediates metformin’s antidiabetic effects on HbA1c in newly-diagnosed individuals with type 2 diabetes.es_ES
dc.description.sponsorshipWe thank the participants in the ANDIS and ANDiU studies, Professor Leif Groop and Maria Sterner for valuable support as well as the SCIBLU genomics facility at Lund University and SciLifeLab (KAW) at Uppsala University for experimental analysis. We thank Gabriella Gremsperger for her help with the ANDIS samples. We thank Tina Rönn, the Nordic Network for Clinical Islet Transplantation (JDRF award 31-2008-413), Human Tissue Laboratory in EXODIAB/Lund University Diabetes Centre, Bioinformatics and Expression Analysis. The authors thank Ylva Wessman and Targ Elgzyri (Scania University Hospital, Malmö, Sweden) and Per-Anders Jansson (Sahlgrenska University Hospital, Göteborg, Sweden) for skilled technical assistance and collection of clinical material from the Twin Monozygotic cohort. This work was supported by the Novo Nordisk foundation, Swedish Research Council (project grant nos. 2020-02191, 2015-2558 and infrastructure grant nos. 2010-5983, 2012-5538 and 2014-6395), Linnaeus grant no. 349-2006-237, Region Skåne (ALF), Marie Skłodowska-Curie grant agreement No 706081 (EpiHope) under Horizon 2020, Hjärt Lung fonden, EFSD, Exodiab (strategic research grant no. 2009-1039), Swedish Foundation for Strategic Research for IRC15-0067, Swedish Diabetes Foundation. S.G.C. was supported by a postdoctoral fellowship (Juan de la Cierva- Incorporación, IJC2019-040796-I).es_ES
dc.titleDNA methylation partially mediates antidiabetic effects of metformin on HbA1c levels in individuals with type 2 diabeteses_ES
dc.description.noteThis is an open access article under the CC BY licensees_ES
dadun.citation.publicationNameDiabetes Research and Clinical Practicees_ES

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