Diabetes medication associates with DNA methylation of metformin transporter genes in the human liver

Given that metformin is the most common pharmacological therapy for type 2 diabetes, understanding the function of this drug is of great importance. Hepatic metformin transporters are responsible for the pharmacologic action of metformin. However, epigenetics in genes encoding metformin transporters has not been fully elucidated. We examined the DNA methylation of these genes in the liver of subjects with type 2 diabetes and tested whether epigenetic alterations associate with diabetes medication, i.e., metformin or insulin plus metformin treatment. DNA methylation in OCT1 encoded by , OCT3 encoded by , and MATE1 encoded by was assessed in the human liver. Lower average and promoter DNA methylation of , , and was found in diabetic subjects receiving just metformin, compared to those who took insulin plus metformin or no diabetes medication. Moreover, diabetic subjects receiving just metformin had a similar DNA methylation pattern in these genes compared to non-diabetic subjects. Notably, DNA methylation was also associated with gene expression, glucose levels, and body mass index, i.e., higher methylation was related to lower expression and to insulin plus metformin treatment, higher fasting glucose levels and higher body mass index. Importantly, metformin treatment did also directly decrease DNA methylation of in hepatocytes cultured in vitro Our study supports that metformin decreases DNA methylation of metformin transporter genes in the human liver. Moreover, higher methylation levels in these genes associate with hyperglycaemia and obesity.