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

García-Calzón, Sonia LU ; Perfilyev, Alexander LU ; Männistö, Ville; de Mello, Vanessa; Nilsson, Emma A LU ; Pihlajamäki, Jussi and Ling, Charlotte LU (2017) In Clinical Epigenetics 9(1). p.1-9
Abstract

Background: 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. Results: DNA 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... (More)

Background: 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. Results: DNA 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. Conclusions: 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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Diabetes medication, Epigenetics, Liver, Metformin, Organic cation transporters, Type 2 diabetes
in
Clinical Epigenetics
volume
9
issue
1
pages
1 - 9
publisher
BioMed Central
external identifiers
  • scopus:85029773075
  • wos:000411415300001
ISSN
1868-7075
DOI
10.1186/s13148-017-0400-0
language
English
LU publication?
yes
id
111ee43c-ee0d-4527-a4fd-eaa2ecec8ba6
date added to LUP
2017-10-10 15:59:08
date last changed
2018-10-16 02:45:42
@article{111ee43c-ee0d-4527-a4fd-eaa2ecec8ba6,
  abstract     = {<p>Background: 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. Results: DNA 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. Conclusions: 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.</p>},
  articleno    = {102},
  author       = {García-Calzón, Sonia and Perfilyev, Alexander and Männistö, Ville and de Mello, Vanessa and Nilsson, Emma A and Pihlajamäki, Jussi and Ling, Charlotte},
  issn         = {1868-7075},
  keyword      = {Diabetes medication,Epigenetics,Liver,Metformin,Organic cation transporters,Type 2 diabetes},
  language     = {eng},
  month        = {09},
  number       = {1},
  pages        = {1--9},
  publisher    = {BioMed Central},
  series       = {Clinical Epigenetics},
  title        = {Diabetes medication associates with DNA methylation of metformin transporter genes in the human liver},
  url          = {http://dx.doi.org/10.1186/s13148-017-0400-0},
  volume       = {9},
  year         = {2017},
}