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Association between the synonymous variant organic cation transporter 3 (OCT3)-1233G>A and the glycemic response following metformin therapy in patients with type 2 diabetes.

ABSTRACT: OBJECTIVES:Organic cation transporter 3 (OCT3) as a high-capacity transporter contribute to the metabolism of metformin. The present study was conducted to determine the genotype frequencies of the variant OCT3-1233G>A (rs2292334) in patients with newly diagnosed type 2 diabetes (T2D) and its relationship with response to metformin. MATERIALS AND METHODS:This study included 150 patients with T2D who were classified into two groups following three months of metformin therapy: responders (by more than 1% reduction in HbA1c from baseline) and nonresponders (less than 1% reduction in HbA1c from baseline). PCR-based restriction fragment length polymorphism (RFLP) served to genotype OCT3-564G>A variant. RESULTS:The parameters such as HbA1c (P<0.001) and BMI (P<0.001) in both patients with GA + AA genotype and GG genotype decreased significantly following 3 months of metformin therapy compared with baseline. The mean reduction in HbA1c levels following 3 months was higher in patients with the A allele (0.77% reduction from baseline) than in those with the homozygous G allele (0.54% reduction from baseline). Also, in GA + AA genotypes compared with GG genotypes, the mean reduction in HbA1c values from baseline was 0.34% for responders and 0.14% for non-responders. CONCLUSION:Considering the roles of genetic variations in the function of metformin transporters, the effect of variations such as 1233G>A in the OCT3, which is a high-capacity transporter widely expressed in various tissues cannot be ignored. Comparing the allele frequencies of OCT3-1233G>A variant in our study and different ethnic populations confirm that the variant is a highly polymorphic variant.

SUBMITTER: Hosseyni-Talei SR

PROVIDER: S-EPMC5378960 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Association between the synonymous variant organic cation transporter 3 (OCT3)-1233G>A and the glycemic response following metformin therapy in patients with type 2 diabetes.

Hosseyni-Talei Seyyedeh Raheleh SR Mahrooz Abdolkarim A Mahrooz Abdolkarim A Hashemi-Soteh Mohammad Bagher MB Ghaffari-Cherati Maryam M Alizadeh Ahad A

Iranian journal of basic medical sciences 20170301 3

<h4>Objectives</h4>Organic cation transporter 3 (OCT3) as a high-capacity transporter contribute to the metabolism of metformin. The present study was conducted to determine the genotype frequencies of the variant OCT3-1233G>A (rs2292334) in patients with newly diagnosed type 2 diabetes (T2D) and its relationship with response to metformin.<h4>Materials and methods</h4>This study included 150 patients with T2D who were classified into two groups following three months of metformin therapy: respo ...[more]

PMID: 28392895

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Project description:Beiging of white adipose tissue (WAT) is a particularly appealing target for therapeutics in the treatment of metabolic diseases through norepinephrine (NE)-mediated signaling pathways. Although previous studies report NE clearance mechanisms via SLC6A2 on sympathetic neurons or proinflammatory macrophages in adipose tissues (ATs), the low catecholamine clearance capacity of SLC6A2 may limit the cleaning efficiency. Here, we report that mouse organic cation transporter 3 (Oct3; Slc22a3) is highly expressed in WAT and displays the greatest uptake rate of NE as a selective non-neural route of NE clearance in white adipocytes, which differs from other known routes such as adjacent neurons or macrophages. We further show that adipocytes express high levels of NE degradation enzymes Maoa, Maob, and Comt, providing the molecular basis on NE clearance by adipocytes together with its reuptake transporter Oct3. Under NE administration, ablation of Oct3 induces higher body temperature, thermogenesis, and lipolysis compared with littermate controls. After prolonged cold challenge, inguinal WAT (ingWAT) in adipose-specific Oct3-deficient mice shows much stronger browning characteristics and significantly elevated expression of thermogenic and mitochondrial biogenesis genes than in littermate controls, and this response involves enhanced ?-adrenergic receptor (?-AR)/protein kinase A (PKA)/cyclic adenosine monophosphate (cAMP)-responsive element binding protein (Creb) pathway activation. Glycolytic genes are reprogrammed to significantly higher levels to compensate for the loss of ATP production in adipose-specific Oct3 knockout (KO) mice, indicating the fundamental role of glucose metabolism during beiging. Inhibition of ?-AR largely abolishes the higher lipolytic and thermogenic activities in Oct3-deficient ingWAT, indicating the NE overload in the vicinity of adipocytes in Oct3 KO adipocytes. Of note, reduced functional alleles in human OCT3 are also identified to be associated with increased basal metabolic rate (BMR). Collectively, our results demonstrate that Oct3 governs ?-AR activity as a NE recycling transporter in white adipocytes, offering potential therapeutic applications for metabolic disorders.

Dataset Information

Association between the synonymous variant organic cation transporter 3 (OCT3)-1233G>A and the glycemic response following metformin therapy in patients with type 2 diabetes.

Publications

Association between the synonymous variant organic cation transporter 3 (OCT3)-1233G>A and the glycemic response following metformin therapy in patients with type 2 diabetes.

Similar Datasets

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