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