Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action.
By Y. Shu, S. Sheardown, C. Brown, R. P. Owen, Shuzhong Zhang, R. Castro, Alexandra G. Ianculescu, L. Yue, J. Lo, E. Burchard and 2 more. Journal of Clinical Investigation, 2007
963 citations recorded by the source corpus.
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.
Subfields: Molecular Biology, Oncology, Surgery
View Paper: https://www.semanticscholar.org/paper/6254ffb1cff1b68a40a13175035a0380d5cd25a6
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Citations in the corpus
- Clinical Pharmacokinetics of Metformin (2011, background): “Metformin is a substrate for OCT1([33,44-46]) and OCT3([32,44]) and the recently discovered and 0.”
- Pharmacogenomics of Drug Metabolizing Enzymes and Transporters: Relevance to Precision Medicine (2016, background): “On the other hand, allele variants G401S, R61C, G465R, and M420del are associated with lower OCT1 activities, which are responsible for the significantly increased renal clearance and reduced glucose-lowering effects of metformin in healthy subjects [156].”
- The mechanisms of action of metformin (2017, background): “[11], metformin was ineffective at improving blood glucose after high-fat feeding [12].”
- Cellular and Molecular Mechanisms of Metformin Action (2020, background): “Polymorphisms of OCT1 are also shown to alter the pharmacokinetics of metformin and reduce therapeutic action; however, whether genetic variation plays a role in the variable clinical response to metformin is still unclear (66-68).”
- Cellular and molecular mechanisms of metformin: an overview. (2012, background): “identified to be involved in the intracellular internalization of the drug [15, 149].”
- Use of Cells Expressing γ Subunit Variants to Identify Diverse Mechanisms of AMPK Activation (2010, methodology): “To confirm that the more rapid effect of metformin in H4IIE cells was due to the expression of OCT1, we investigated the effects of quinidine, a high-affinity substrate for OCT1 that acts as a competitive inhibitor.”
- Membrane transporters in drug development (2010, background): “These are in addition to various human embryonic kidney (HEK293) cell lines expressing recombinant OCT”
- The LKB1-AMPK pathway: metabolism and growth control in tumor suppression (2009, background): “Similarly, genetic polymorphisms in the cell surface transporter organic cation transporter 1 ( OCT1 ), which is required for efficient metformin uptake in hepatocytes, have been shown to underlie metformin resistance in some patients with type 2 diabete”