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

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

doi:10.1172/jci30558

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.

Highlights

Metabolic syndrome and its pathological sequela, type 2 diabetes, have become major health problems in the world
We examined the effects of nonsynonymous Organic cation transporter 1 (OCT1) polymorphisms on metformin uptake and response in cellular assays
organic cation transporters (OCTs) activity is a determinant of metformin response in cell lines

Summary

Introduction

Metabolic syndrome and its pathological sequela, type 2 diabetes, have become major health problems in the world. The biguanide metformin is widely used as a first-line therapy for the treatment of type 2 diabetes [1]. Metformin ameliorates hyperglycemia by reducing gastrointestinal glucose absorption and hepatic glucose production and by improving glucose utilization [1]. The molecular mechanisms underlying metformin action appear to be related to its activation (phosphorylation) of the so-called energy sensor AMP-activated protein kinase (AMPK), which suppresses glucagon-stimulated glucose production and causes an increase in glucose uptake in muscle and in hepatic cells [4, 5]. The activation of AMPK may be responsible for the improvement of lipid metabolism by metformin [4]. Serine-threonine kinase 11 (STK11/LKB1), which phosphorylates AMPK, has been reported to be involved in metformin effects [6, 7]

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