Dataset Information

Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin.

ABSTRACT: Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 × 10(-14)) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine.

SUBMITTER: Zhou K

PROVIDER: S-EPMC5007158 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin.

Zhou Kaixin K Yee Sook Wah SW Seiser Eric L EL van Leeuwen Nienke N Tavendale Roger R Bennett Amanda J AJ Groves Christopher J CJ Coleman Ruth L RL van der Heijden Amber A AA Beulens Joline W JW de Keyser Catherine E CE Zaharenko Linda L Rotroff Daniel M DM Out Mattijs M Jablonski Kathleen A KA Chen Ling L Javorský Martin M Židzik Jozef J Levin Albert M AM Williams L Keoki LK Dujic Tanja T Semiz Sabina S Kubo Michiaki M Chien Huan-Chieh HC Maeda Shiro S Witte John S JS Wu Longyang L Tkáč Ivan I Kooy Adriaan A van Schaik Ron H N RHN Stehouwer Coen D A CDA Logie Lisa L Logie Lisa L Sutherland Calum C Klovins Janis J Pirags Valdis V Hofman Albert A Stricker Bruno H BH Motsinger-Reif Alison A AA Wagner Michael J MJ Innocenti Federico F 't Hart Leen M LM Holman Rury R RR McCarthy Mark I MI Hedderson Monique M MM Palmer Colin N A CNA Florez Jose C JC Giacomini Kathleen M KM Pearson Ewan R ER

Nature genetics 20160808 9

Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 × 10(-14)) greater metformin-induced reduction in hemoglob ...[more]

PMID: 27500523

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Project description:ObjectiveThis study aimed to evaluate whether the M420del variants of SLC22A1 (rs72552763) is associated with metformin treatment response in Ethiopian patients with type 2 diabetes mellitus (T2DM).Patients and methodsA prospective observational cohort study was conducted on 86 patients with T2DM who had been receiving metformin monotherapy for <1 year. Patients showing ≥0.5% reduction in HbA1c levels from baseline within 3 months and remained low for at least another 3 months were defined as responders while those patients with <0.5% reduction in HbA1c levels and/or those whom started a new class of glucose-lowering drug(s) because of unsatisfactory reduction were defined as non-responders. In addition, good glycemic control was observed when HbA1c ≤7.0%, and the above values were regarded as poor. Genotyping of rs72552763 SNP was performed using TaqMan® Drug Metabolism Enzyme Genotyping Assay and its association with metformin response and glycemic control were assessed by measuring the change in HbA1c and fasting blood glucose levels using Chi-square, logistic regression and Mann-Whitney U-test. Statistical significance was set at p <0.05.ResultsThe minor allele frequency of the rs72552763 SNP of SLC22A1 was 9.3%. Metformin response was significantly higher in deletion_GAT (del_G) genotypes as compared to the wild-type GAT_GAT (G_G) genotypes. Furthermore, a significantly lower median treatment HbA1 level was found in del_G genotypes as compared to G_G genotypes. However, the association of rs72552763 with metformin response was not replicated at the allele level. In contrast, the minor del_allele was significantly associated with good glycemic control compared to the G_allele, though not replicated at del_G genotypes level.ConclusionThis study demonstrated that metformin response was significantly higher in study participants with a heterozygous carrier of M420del variants of SLC22A1 as compared to the wild-type G_G genotypes after 3 months of treatment.

Dataset Information

Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin.

Publications

Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin.

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