Genetic polymorphisms of organic cation transporter 1 (OCT1) and responses to metformin therapy in individuals with type 2 diabetes

Abstract

Background:Metformin is one of the most commonly used drugs for the treatment of type 2 diabetes mellitus (T2DM). Despite its widespread use, there are considerable interindividual variations in metformin response, with about 35% of patients failing to achieve initial glycemic control. These variabilities that reflect phenotypic differences in drug disposition and action may indeed be due to polymorphisms in genes that regulate pharmacokinetics and pharmacodynamics of metformin. Moreover, interethnic differences in drug responses in some cases correspond to substantial differences in the frequencies of the associated pharmacogenomics risk allele.Aim:This study aims to highlight and summarize the overall effects of organic cation transporter 1(OCT1) polymorphisms on therapeutic responses to metformin and to evaluate the potential role of such polymorphisms in interethnic differences in metformin therapy.Methods:We conducted a systematic review according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. We searched for PubMed/MEDLINE, Embase, and CINAHL, relevant studies reporting the effects of OCT1 polymorphisms on metformin therapy in T2DM individuals. Data were extracted on study design, population characteristics, relevant polymorphisms, measure of genetic association, and outcomes. The presence of gastrointestinal side effects, glycated hemoglobin A1 (HbA1c) levels, fasting plasma glucose (FPG), and postprandial plasma glucose (PPG) concentrations after treatment with metformin were chosen as measures of the metformin responses. This systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO).Results:According to the data extracted, a total of 34 OCT1 polymorphisms were identified in 10 ethnic groups. Significant differences in the frequencies of common alleles were observed among these groups. Met408Val (rs628031) variant was the most extensively explored with metformin responses. Although some genotypes and alleles have been associated with deleterious effects on metformin response, others indeed, exhibited positive effects.Conclusion:Genetic effects of OCT1 polymorphisms on metformin responses were population specific. Further investigations in other populations are required to set ethnicity-specific reference for metformin responses and to obtain a solid basis to design personalized therapeutic approaches for T2DM treatment.

Pharmacogenetics of Type 2 Diabetes—Progress and Prospects

“…In SLC22A1 gene knockout mice, the liver concentration of metformin was 30 times lower than in mice with normal functioning OCT1 transporters [ 30 ]. There were many studies of the SLC22A1 genetic polymorphisms in different populations but results on the effects of SLC22A1 polymorphisms on metformin therapeutic responses were rather contradictory [ 49 ]. Shu and colleagues suggested that genetic variation in SLC22A1 may contribute to variation in response to metformin and they performed a series of experiments to analyze whether variants rs12208357 ( R61C ), rs34130495 ( G401S ), rs72552763 ( 420del ) and rs34059508 ( G465R ) contribute to reduced therapeutic response to metformin clinically.…”

Of mice and men: Is there a future for metformin in the treatment of hepatic steatosis?

“…Finally, genetic variation in humans may also be a confounding factor; for example, polymorphisms in the metformin transporter OCT1 have been described (as discussed earlier), with the most common being rs628031 (A > G), which reduces OCT1 expression levels and may affect uptake of metformin into tissues . Additionally, the presence of the PNPLA3 gene variant rs738409 (C > G) is associated with increased IHTAG content in humans and may also act as a confounding factor in how metformin has an impact on hepatic fat content and metabolism.…”

Significance of Metformin Use in Diabetic Kidney Disease

“…It enters hepatocytes through organic cationic transporter (OCT) 1, as shown by a study demonstrating a reduced metformin uptake in hepatocytes of OCT1-deficient mice [ 28 ]. In addition, genetic polymorphisms of OCT1 in humans that determine responses to metformin have been reported [ 29 ]. Metformin is excreted via the urine, which is mediated by renal OCT1 and OCT2 on the basolateral membrane of proximal tubule cells and multidrug and toxin extrusion (MATE) 1 on the apical membrane [ 30 , 31 , 32 ].…”