Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action
Yan Shu, Steven A. Sheardown, Chaline Brown, Ryan P. Owen, Shuzhong Zhang, Richard A. Castro, Alexandra G. Ianculescu, Lin Yue, Joan C. Lo, Esteban G. Burchard, Claire M. Brett, Kathleen M. Giacomini
Yan Shu, Steven A. Sheardown, Chaline Brown, Ryan P. Owen, Shuzhong Zhang, Richard A. Castro, Alexandra G. Ianculescu, Lin Yue, Joan C. Lo, Esteban G. Burchard, Claire M. Brett, Kathleen M. Giacomini
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Research Article

Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action

Abstract

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.

Authors

Yan Shu, Steven A. Sheardown, Chaline Brown, Ryan P. Owen, Shuzhong Zhang, Richard A. Castro, Alexandra G. Ianculescu, Lin Yue, Joan C. Lo, Esteban G. Burchard, Claire M. Brett, Kathleen M. Giacomini

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Figure 8

OCT1 genetic variants are associated with different responses to metformin in healthy human volunteers.

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OCT1 genetic variants are associated with different responses to metform...
(A) The time course of plasma glucose concentrations for a baseline OGTT without metformin treatment in healthy subjects having only reference OCT1 alleles (n = 8) and those having at least 1 reduced-function OCT1 allele (n = 12). The data are expressed as mean ± SEM. (B) The time course of plasma glucose concentrations for OGTT after metformin treatment in the same healthy subjects represented in A. The data are expressed as mean ± SEM; *P < 0.05 compared with volunteers with only reference OCT1 alleles (unpaired Student’s t test). (C) The glucose exposure with OGTT (AUC) after metformin treatment for healthy subjects represented in B. The horizontal lines represent mean values for the 2 groups. The mean value for volunteers with only reference OCT1 alleles is significantly lower than that for the variant group. P = 0.004 (unpaired Student’s t test). (D) The time course of insulin levels during the OGTT after metformin administration in the same healthy individuals represented in A. The data are expressed as mean ± SEM; *P < 0.05 compared with individuals with only OCT1-reference alleles (unpaired 1-tailed Student’s t test).