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 9

Mechanism of metformin action in cells.

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Mechanism of metformin action in cells. By controlling the intracellular...
By controlling the intracellular concentrations, OCT1 is a direct determinant of metformin pharmacological effects in the liver (bold arrow). Passive diffusion and other transporters may account for small portion of hepatic uptake of metformin (dashed arrow). Other transporters may control metformin uptake into other tissues, such as skeletal muscle. Factors such as genetic variation in transporter genes may alter transporter activity and thus metformin response. LKB, alias of serine-threonine kinase 11 (STK11); PGC-1α, peroxisome proliferator activated receptor γ coactivator 1 α; TORC2, target of rapamycin complex 2.