Endocrine Abstracts (2011) 26 OC4.3

Association of genetic polymorphisms in the organic cation transporters OCT1, OCT2 and multidrug and toxin extrusion 1 transporter protein with the metformin intolerance and weight lowering in patients of type 2 diabetes

L Tarasova1, J Klovins1, I Kalnina1, A Bumbure2, R Ritenberga2, K Geldnere2, L Nikitina-Zake1 & V Pirags2

1Latvian Biomedical Research and Study Center, Riga, Latvia; 2Department of Endocrinology, Pauls Stradins Clinical University Hospital, University of Latvia, Riga, Latvia.

Objective: Metformin is one of the most widely used drugs in primary therapy for the treatment of type 2 diabetes (T2D). Despite its overall efficiency in T2D treatment metformin shows significant proportion of patients suffering from number of side effects. So far number of polymorphisms mainly in genes coding for various metformin transporter proteins have been described in association with metformin efficiency. However, no information exists on influence of genetic variation of metformin transporters on metformin side effects. OCT1, OCT2 and MATE1 transporters are involved in pharmacokinetics of metformin. In this study, we assessed whether 5 SNP and 2 indel polymorphisms are associated with metformin side effects in Latvian patients of type 2 diabetes.

Methods: We used information from Genome Database of Latvian Population and METFOGENE study to identify all metformin users and their response to metformin intake. Polymorphisms in SLC22A1 – rs12208357, rs34059508, rs628031; rs36056065 and rs72552763; SLC22A2 – rs316019; SLC47A1 – rs2289669 were compared between 74 type 2 diabetes patients with metformin intolerance and 236 metformin users without symptoms of metformin intolerance.

Results: We found a statistically significant association between A allele of rs628031 (P=0.008175, OR=0.558, CI 95% (0.3848–0.8703))) as well as 8 bp insertion (rs36056065) (P=0.008527, OR=0.546, CI 95% (0.3929–0.8749)) and presence of metformin intolerance. Additionally carriers of rs2289669 A allele (SLC47A1) displayed significantly lower (P=0.002114) mean BMI (32.67 kg/m2) compared to wt GG genotype (36.49 kg/m2) among regular metformin users.

Conclusion: Genetic variation in OCT1 encoded by SLC22A1 may predispose to increased incidence of metformin intolerance in patients with type 2 diabetes. Our results may also suggest that rs2289669 located in SLC47A1 gene coding for MATE1 transporter may be associated with increased efficiency of metformin effect on the weight lowering, which is in accordance with MATE1 function in hepatocytes.