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DNA methylation partially mediates antidiabetic effects of metformin on HbA1c levels in individuals with type 2 diabetes

García-Calzón, Sonia LU ; Schrader, Silja LU ; Perfilyev, Alexander LU orcid ; Martinell, Mats ; Ahlqvist, Emma LU and Ling, Charlotte LU orcid (2023) In Diabetes Research and Clinical Practice 202.
Abstract

Aims: 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 newly-diagnosed 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... (More)

Aims: 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 newly-diagnosed 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.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Epigenetics, Epigenomics, EWAS, Glycemia, Mechanism, Pharmacoepigenetics, Therapy
in
Diabetes Research and Clinical Practice
volume
202
article number
110807
publisher
Elsevier
external identifiers
  • pmid:37356726
  • scopus:85163830480
ISSN
0168-8227
DOI
10.1016/j.diabres.2023.110807
language
English
LU publication?
yes
id
08b7fa2b-84a1-4a64-8751-6064c4b63bdd
date added to LUP
2023-09-06 14:30:57
date last changed
2024-04-20 02:56:20
@article{08b7fa2b-84a1-4a64-8751-6064c4b63bdd,
  abstract     = {{<p>Aims: 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 newly-diagnosed 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 &lt; 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 &lt; 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.</p>}},
  author       = {{García-Calzón, Sonia and Schrader, Silja and Perfilyev, Alexander and Martinell, Mats and Ahlqvist, Emma and Ling, Charlotte}},
  issn         = {{0168-8227}},
  keywords     = {{Epigenetics; Epigenomics; EWAS; Glycemia; Mechanism; Pharmacoepigenetics; Therapy}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Diabetes Research and Clinical Practice}},
  title        = {{DNA methylation partially mediates antidiabetic effects of metformin on HbA1c levels in individuals with type 2 diabetes}},
  url          = {{http://dx.doi.org/10.1016/j.diabres.2023.110807}},
  doi          = {{10.1016/j.diabres.2023.110807}},
  volume       = {{202}},
  year         = {{2023}},
}