Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action
Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action
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DOI：
10.1172/jci30558
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发表时间：
2007-05-01
影响因子：
15.9
通讯作者：
Giacomini, Kathleen M.
中科院分区：
文献类型：
--
作者：
Shu, Yan;Sheardown, Steven A.;Giacomini, Kathleen M.
二甲双胍是治疗2型糖尿病最广泛的处方药之一。有机阳离子转运体1(OCT1)在肝脏对二甲双胍的摄取中起作用，但它在药物治疗效果中的作用尚不清楚，其中涉及AMP激活的蛋白激酶(AMPK)的激活。最近的研究表明，人类OCT1基因具有高度的多态性。我们调查了OCT1是否在二甲双胍的作用中起作用，以及OCT1基因多态个体是否降低了对药物的反应。在小鼠肝细胞中，Oct1基因的缺失导致二甲双胍对AMPK磷酸化和糖异生的影响减弱。在Oct1缺陷小鼠中，二甲双胍的降糖作用被完全消除。鉴定出OCT1的7个非同义多态，显示出对二甲双胍摄取减少。值得注意的是，OCT1-420del(在美国白人中等位基因频率约为20%)，以前被证明对模型底物具有正常活性，但降低了对二甲双胍的活性。在临床研究中，在携带OCT1功能多态降低的个体中，二甲双胍对糖耐量试验的影响显著降低。总而言之，这些数据表明OCT1对二甲双胍的治疗作用很重要，OCT1的遗传变异可能会导致药物反应的变化。
Metformin is among the most widely prescribed drugs for the treatment of type 2 diabetes. Organic cation transporter 1 (OCT1) plays a role in the hepatic uptake of metformin, but its role in the therapeutic effects of the drug, which involve activation of AMP-activated protein kinase (AMPK), is unknown. Recent studies have shown that human OCT1 is highly polymorphic. We investigated whether OCT1 plays a role in the action of metformin and whether individuals with OCT1 polymorphisms have reduced response to the drug. In mouse hepatocytes, deletion of Oct1 resulted in a reduction in the effects of metformin on AMPK phosphorylation and gluconeogenesis. In Oct1-deficient mice the glucose-lowering effects of metformin were completely abolished. Seven nonsynonymous polymorphisms of OCT1 that exhibited reduced uptake of metformin were identified. Notably, OCT1-420del (allele frequency of about 20% in white Americans), previously shown to have normal activity for model substrates, had reduced activity for metformin. In clinical studies, the effects of metformin in glucose tolerance tests were significantly lower in individuals carrying reduced function polymorphisms of OCT1. Collectively, the data indicate that OCT1 is important for metformin therapeutic action and that genetic variation in OCT1 may contribute to variation in response to the drug.