Abstract
BackgroundGiven 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.ResultsDNA methylation in OCT1 encoded by SLC22A1, OCT3 encoded by SLC22A3, and MATE1 encoded by SLC47A1 was assessed in the human liver. Lower average and promoter DNA methylation of SLC22A1, SLC22A3, and SLC47A1 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 SLC22A3 methylation was related to lower SLC22A3 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 SLC22A1 in hepatocytes cultured in vitro.ConclusionsOur 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.
Highlights
Given that metformin is the most common pharmacological therapy for type 2 diabetes, understanding the function of this drug is of great importance
As metformin’s primary action is considered to be in the liver, hepatic uptake by organic cation transporters (OCT1 encoded by SLC22A1 and OCT3 encoded by SLC22A3) and secretion to the bile through an efflux transporter (MATE1 encoded by SLC47A1) are essential for the pharmacological effect of this drug [1]
We examined if DNA methylation in the SLC22A1, SLC22A3, and SLC47A1 genes was different in the human liver according to diabetes medication
Summary
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. 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. Metformin is the most common pharmacological therapy for type 2 diabetes (T2D). As metformin’s primary action is considered to be in the liver, hepatic uptake by organic cation transporters (OCT1 encoded by SLC22A1 and OCT3 encoded by SLC22A3) and secretion to the bile through an efflux transporter (MATE1 encoded by SLC47A1) are essential for the pharmacological effect of this drug [1]. Genetics of metformin transporters have been described, epigenetic regulation of these genes is less studied. Higher DNA methylation of SLC22A1 was associated with decreased expression of this gene in hepatocellular carcinoma.
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