DNA methylation of the glucagon-like peptide 1 receptor (GLP1R) in human pancreatic islets

BMC Medical Genetics

Charlotte Ling¹  Marloes Dekker Nitert²  Claes B Wollheim³  Clare L Kirkpatrick³  Tasnim Dayeh¹  Elin Hall¹ 

[1]Department of Clinical Sciences, Lund University Diabetes Centre, CRC, Lund University, Scania University Hospital, Malmö, Sweden

[2]University of Queensland Centre for Clinical Research, Brisbane, Australia

[3]Department of Cell Physiology and Metabolism, University Medical Centre, 1 rue Michel-Servet, 1211, Geneva 4, Switzerland

关键词: DNMT3;    DNMT1;    β cells;    α cells;    Pancreatic islet;    Type 2 diabetes;    GLP1R;    Glucagon-like peptide 1 receptor;    Epigenetics;    DNA methylation;   

Others  :  1127653
DOI  :  10.1186/1471-2350-14-76

 received in 2012-11-13, accepted in 2013-07-18,  发布年份 2013

【 摘 要 】

Background

Insulin secretion is enhanced upon the binding of Glucagon-like peptide-1 (GLP-1) to its receptor (GLP1R) in pancreatic β cells. Although a reduced expression of GLP1R in pancreatic islets from type 2 diabetic patients and hyperglycaemic rats has been established, it is still unknown if this is caused by differential DNA methylation of GLP1R in pancreatic islets of type 2 diabetic patients.

Methods

In this study, DNA methylation levels of 12 CpG sites close to the transcription start site of GLP1R were analysed in pancreatic islets from 55 non-diabetic and 10 type 2 diabetic human donors as well as in β and α cells isolated from human pancreatic islets. DNA methylation of GLP1R was related to GLP1R expression, HbA_1c levels and BMI. Moreover, mRNA expression of MECP2, DNMT1, DNMT3A and DNMT3B was analysed in pancreatic islets of the non-diabetic and type 2 diabetic donors.

Results

One CpG unit, at position +199 and +205 bp from the transcription start site, showed a small increase in DNA methylation in islets from donors with type 2 diabetes compared to non-diabetic donors (0.53%, p=0.02). Furthermore, DNA methylation levels of one CpG site located 376 bp upstream of the transcription start site of GLP1R correlated negatively with GLP1R expression (rho=−0.34, p=0.008) but positively with BMI and HbA_1c (rho=0.30, p=0.02 and rho=0.30, p=0.03, respectively). This specific CpG site is located in an area with known SP1 and SP3 transcription factor binding sites. Moreover, when we compared the DNA methylation of the GLP1R promoter in isolated human β and α cells, we found that it was higher in α- compared with β-cells (p=0.009). Finally, there was a trend towards decreased DNMT3A expression (p=0.056) in type 2 diabetic compared with non-diabetic islets.

Conclusions

Together, our study shows that while BMI and HbA_1c are positively associated with DNA methylation levels of GLP1R, its expression is negatively associated with DNA methylation of GLP1R in human pancreatic islets.

【 授权许可】

   
2013 Hall et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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