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.

Regulation of hepatic glucose production and AMPK by AICAR but not by metformin depends on drug uptake through the equilibrative nucleoside transporter 1 (ENT1)

“…Using an additional control, we did not observe any major degradation products of AICAR in the medium, indicating that AICAR depletion is most likely the result of cellular uptake. The difference between AICAR and metformin sensitivity to NBMPR is consistent with metformin being taken into the cell via OCT transporters, as reported previously 19, 20. Our findings may explain previous observations that required the use of very high (2 mM) concentrations of AICAR to inhibit 8CPT‐cAMP‐induced HGP 11.…”

“…Metformin and AICAR are both activators of AMPK; however, earlier studies, including some carried out in mice where the catalytic subunits of AMPK are genetically ablated, demonstrated that suppression of HGP occurs independently of AMPK activation 13, 14, 15, 17, 18. Metformin is transported across hepatocyte cell membranes, at least in part, by an organic cation transporter (OCT) family of transporters 18, 19, 20. Previous studies using siRNA determined that AICAR is transported by ENT1 and CNT3 into human macrophages,21 whereas AICAR uptake into hepatocytes and its role concerning HGP is less clear.…”

Transporters Involved in Metformin Pharmacokinetics and Treatment Response

“…In particular, the liver is a major site of action for metformin, which reduces hepatic glucose production 1,3,32 . OCT1 and OCT3 are expressed on the sinusoidal membrane of hepatocytes and play a major role in the uptake of metformin from blood into the hepatocytes 59 . In 2002, elegant studies from the Sugiyama group showed that OCT1 is responsible for the hepatic uptake and intestinal distribution of metformin 60,61 Further, reduced hepatic metformin concentrations have been shown to affect metformin response in mice 62 .…”

Finding type 2 diabetes causal single nucleotide polymorphism combinations and functional modules from genome-wide association data

“…In addition, signal transducer and activator of transcription 5 (STAT5) activity in pancreatic β-cells showed susceptibility to T2D [46]. Organic cation transporter 1 (OCT1) is related to the hepatic uptake of metformin, which is one of the most used drugs for T2D, and the genetic variation in the OCT1 gene can affect individual drug response to metformin [47]. From GO biological process category, angiogenesis is the most significant functional module, with an FDR value of 3.15E-02, and suppressed angiogenesis is one of the characteristic features of T2D complication [48].…”