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
J Clin Invest.
2007;
117(5):1422–1431
doi:10.1172/JCI30558
This article Copyright © 2007, The American Society for Clinical Investigation
Abstract
|
Full text
|
PDF
|
Supplemental material
M
etformin 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.
