TY - JOUR
T1 - DNA methylation partially mediates antidiabetic effects of metformin on HbA1c levels in individuals with type 2 diabetes
AU - García-Calzón, Sonia
AU - Schrader, Silja
AU - Perfilyev, Alexander
AU - Martinell, Mats
AU - Ahlqvist, Emma
AU - Ling, Charlotte
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - Epigenetics
KW - Epigenomics
KW - EWAS
KW - Glycemia
KW - Mechanism
KW - Pharmacoepigenetics
KW - Therapy
U2 - 10.1016/j.diabres.2023.110807
DO - 10.1016/j.diabres.2023.110807
M3 - Article
C2 - 37356726
AN - SCOPUS:85163830480
SN - 0168-8227
VL - 202
JO - Diabetes Research and Clinical Practice
JF - Diabetes Research and Clinical Practice
M1 - 110807
ER -