ECE2015 Eposter Presentations Diabetes (complications & therapy) (143 abstracts)
Association of SNPs in the intergenic region of OCT2 and OCT3 with short-term efficiency of metformin monotherapy in the type 2 diabetes patients
Janis Klovins 1 , Linda Zaharenko 1 , Kristine Geldnere 2 , Ilze Konrade 5 , Solveiga Grinberga 4 , Osvalds Pugovics 4 , Ineta Kalnina 1 & Valdis Pirags 2,
1Latvian Biomedical Research and Study Centre, Ratsupites 1, LV1067 Riga, Latvia; 2Department of Endocrinology, Pauls Stradins Clinical University Hospital, Pilsonu Str. 13, LV1002 Riga, Latvia; 3Faculty of Medicine, University of Latvia, Sarlotes Str. 1a, LV1001 Riga, Latvia; 4Latvian Institute of Organic Synthesis, Riga, Latvia; 5Department of Medicine, Riga East Clinical University Hospital, Riga Stradins University, Riga, Latvia.
Clinical response to metformin is highly variable in type 2 diabetes (T2D) patients highlighting the need for identification of genetic components affecting the efficiency of metformin therapy. Aim of this study was to evaluate the role of systematically selected tagSNPs from genomic regions coding for six organic cation transporters implicated in transport of metformin with respect to the short-term efficiency. The study involved 102 drug naïve newly diagnosed T2D patients who were treated with metformin monotherapy for 3 months. We genotyped 104 tagSNPs from six metformin transporter genes coding for OCT1, OCT2, OCT3, MATE1, MATE2, and PMAT. Minor alleles of rs3119309, rs7757336l, and rs2481030 located in the intergenic region between SLC22A2 (OCT1) and SLC22A3 (OCT3) were significantly associated (P=1.849×10−6 to 2.663×10−5) with metformin inefficiency defined as no decrease of HbA1c blood level after 3 months of treatment. Carriers of risk alleles were 8.4 times more likely to exhibit non-responder phenotype than participants with wild type alleles. Pharmacokinetic study in 15 healthy participants was conducted to investigate the effects of identified polymorphisms on kinetics of plasma and erythrocytes metformin after acute administration in healthy subjects. Subjects with combined risk alleles of polymorphisms rs3119309, rs7757336, and rs2481030 showed strongly reduced AUC∞ of metformin exposure. In conclusion we have identified for the first time strong association between metformin non-response and three SNPs located in the 5′ flanking regions of the SLC22A2 (OCT2) and SLC22A3 (OCT3). These results indicate the importance of metformin transporters in the short- term efficiency of metformin.
Disclosure: This work was supported by State Research Programme BIOMEDICINE.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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