、、和多态性与2型糖尿病患者二甲双胍疗效的关联
Association of , , , and Polymorphisms with Metformin Efficacy in Type 2 Diabetic Patients.
作者信息
Chen Peixian, Cao Yumin, Chen Shenren, Liu Zhike, Chen Shiyi, Guo Yali
机构信息
Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Shantou University Medical College, Shantou 515000, China.
Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing 100191, China.
出版信息
Biomedicines. 2022 Oct 12;10(10):2546. doi: 10.3390/biomedicines10102546.
Response to metformin, first-line therapy for type 2 diabetes mellitus (T2DM), exists interindividual variation. Considering that transporters belonging to the solute carrier (SLC) superfamily are determinants of metformin pharmacokinetics, we evaluated the effects of promoter variants in organic cation transporter 1 (OCT1) ( rs628031), OCT2 ( rs316019), multidrug and toxin extrusion protein 1 (MATE1) ( rs2289669), and MATE2 ( rs12943590) on the variation in metformin response. The glucose-lowering effects and improvement of insulin resistance of metformin were assessed in newly diagnosed, treatment-naive type 2 diabetic patients of Han nationality in Chaoshan China ( = 93) receiving metformin. Fasting plasma glucose (FPG), fasting insulin (FINS), glycated hemoglobin A1 (HbA1), homeostasis model assessment-insulin sensitivity (HOMA-IS), and homeostasis model assessment-insulin resistance (HOMA-IR) were the main metformin efficacy measurements. There were significant correlations between both rs2289669 and rs12943590 and the efficacy of metformin in individuals with T2DM. In normal weight T2DM patients, significant associations between the AA and GG genotypes of the rs2289669 variant of and a greater reduction in FINS and HOMA-IR were detected. A significant correlation was observed between the AG genotype of the rs12943590 polymorphism of and a greater reduction in HOMA-IR. Gene-environment interaction analysis showed that in the FINS interaction model, the second-order of dose30_g- rs12943590 was statistically significant. The variants of rs2289669 and rs12943590 could be predictors of insulin resistance in type 2 diabetic patients treated with metformin. The second-order interaction of dose30_g- rs12943590 may have a significant effect on FINS in patients with T2DM on metformin treatment. These findings suggest that promoter variants of and are important determinants of metformin transport and response in type 2 diabetes mellitus.
二甲双胍作为2型糖尿病（T2DM）的一线治疗药物，个体间存在反应差异。鉴于溶质载体（SLC）超家族的转运蛋白是二甲双胍药代动力学的决定因素，我们评估了有机阳离子转运体1（OCT1）（rs628031）、OCT2（rs316019）、多药和毒素外排蛋白1（MATE1）（rs2289669）以及MATE2（rs12943590）启动子变异对二甲双胍反应差异的影响。在中国潮汕地区新诊断的、未接受过治疗的汉族2型糖尿病患者（n = 93）中，评估了二甲双胍的降糖效果和胰岛素抵抗改善情况。空腹血糖（FPG）、空腹胰岛素（FINS）、糖化血红蛋白A1（HbA1）、稳态模型评估胰岛素敏感性（HOMA - IS）和稳态模型评估胰岛素抵抗（HOMA - IR）是二甲双胍疗效的主要测量指标。rs2289669和rs12943590与T2DM个体中二甲双胍的疗效均存在显著相关性。在正常体重的T2DM患者中，检测到rs2289669变异的AA和GG基因型与FINS和HOMA - IR的更大降低之间存在显著关联。观察到rs12943590多态性的AG基因型与HOMA - IR的更大降低之间存在显著相关性。基因 - 环境相互作用分析表明，在FINS相互作用模型中，dose30_g - rs12943590的二阶项具有统计学意义。rs2289669和rs12943590变异可能是接受二甲双胍治疗的2型糖尿病患者胰岛素抵抗的预测指标。dose30_g - rs12943590的二阶相互作用可能对接受二甲双胍治疗的T2DM患者的FINS有显著影响。这些发现表明，MATE1和MATE2的启动子变异是2型糖尿病中二甲双胍转运和反应的重要决定因素。
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