Role of human organic cation transporter-1 (OCT-1/SLC22A1) in modulating the response to metformin in patients with type 2 diabetes
Tóm tắt
Organic cation transporter 1 primarily governs the action of metformin in the liver. There are considerable inter-individual variations in metformin response. In light of this, it is crucial to obtain a greater understanding of the influence of OCT1 expression or polymorphism in the context of variable responses elicited by metformin treatment. We observed that the variable response to metformin in the responders and non-responders is independent of isoform variation and mRNA expression of OCT-1. We also observed an insignificant difference in the serum metformin levels of the patient groups. Further, molecular docking provided us with an insight into the hotspot regions of OCT-1 for metformin binding. Genotyping of these regions revealed SNPs 156T>C and 1222A>G in both the groups, while as 181C>T and 1201G>A were found only in non-responders. The 181T>C and 1222A>G changes were further found to alter OCT-1 structure in silico and affect metformin transport in vitro which was illustrated by their effect on the activation of AMPK, the marker for metformin activity. Taken together, our results corroborate the role of OCT-1 in the transport of metformin and also point at OCT1 genetic variations possibly affecting the transport of metformin into the cells and hence its subsequent action in responders and non-responders.
Tài liệu tham khảo
Hayer M, Bonisch H, Bruss M. Molecular cloning, functional characterization and genomic organization of four alternatively spliced isoforms of the human organic cation transporter 1 (hOCT1/SLC22A1). Ann Hum Genet. 1999;63:473–82.
Shu Y, Sheardown SA, Brown C, et al. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest. 2007;117:1422–31.
Cook MN, Girman CJ, Stein PP, et al. Initial monotherapy with either metformin or sulphonylureas often fails to achieve or maintain current glycaemic goals in patients with Type 2 diabetes in UK primary care. Diabet Med. 2007;24:350–8.
Florez JC. Does metformin work for everyone? A genome-wide association study for metformin response. Curr Diab Rep. 2011;11:4679.
Van Leeuwen N, Swen JJ, Guchelaar HJ, et al. The role of pharmacogenetics in drug disposition and response of oral glucose lowering drugs. Clin Pharmacokinet. 2013;52:833–54.
Seitz T, Stalmann R, Dalila N, et al. Global genetic analyses reveal strong inter-ethnic variability in the loss of activity of the organic cation transporter OCT1. Genome Med. 2015;7:1–23.
Dujic T, Zhou K, Donnelly LA, et al. Association of organic cation transporter 1 with intolerance to metformin in type 2 diabetes: a GoDARTS study. Diabetes. 2015;64:1786–93.
Nies T, Koepsell H, Winter S, et al. Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver. Hepatology. 2009;50:1227–40.
Hess B, Kutzner C, Van Der Spoel D, Lindahl E. GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput. 2008;4(3):435–47.
GoDarts Group UDPS, Wellcome Trust Case Control C. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nature genetics 2011, 43, 117–20.
Florez JC, Jablonski KA, Taylor A, et al. The C allele of ATM rs11212617 does not associate with metformin response in the Diabetes Prevention Program. Diabetes Care. 2012;35:1864–7.
Van Leeuwen N, Nijpels G, Becker ML, et al. A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts. Diabetologia. 2012;55:1971–7.
Sherifali D, Nerenberg K, Pullenayegum E, Cheng JE, Gerstein HC. The effect of oral antidiabetic agents on A1C levels. Diabetes Care. 2010;33:1859–64.
Abdolkarim Mahrooz, Hassan Parsanasab, Mohammad Bagher Hashemi-Soteh et al. The role of clinical response to metformin in patients newly diagnosed with type 2 diabetes: a monotherapy study. Clin Exp Med 2015, 15(2), 159–165.
Bakura B, Das M, Pattanayak AK, et al. Inter-patient Variability in Clinical Efficacy of Metformin in Type 2 Diabetes Mellitus Patients in West Bengal. India J Metabolic Synd. 2016;5:198.
Li Q, Li C, Li H, et al. STK11 rs2075604 Polymorphism Is Associated with Metformin Efficacy in Chinese Type 2 Diabetes Mellitus. International Journal of Endocrinology. 2017;2017:1–6.
Nies AT, Hofmann U, Resch C, et al. Proton pump inhibitors inhibit metformin uptake by organic cation transporters (OCTs). PLoS ONE. 2011;6:e22163.
Hirst JA, Farmer AJ, Ali R, Roberts NW, Stevens RJ. Quantifying the Effect of Metformin Treatment and Dose on Glycemic Control. Diabetes Care. 2012;35:446–54.
Kousei K, Hiroyuki I, Shinsuke N, et al. Effects of dosage and dosing frequency on the efficacy and safety of high-dose metformin in Japanese patients with type 2 diabetes mellitus. J Diabetes Investig. 2018;9:587–93.
Kerb R, Brinkmann U, Chatskaia N, et al. Identification of genetic variations of the human organic cation transporter hOCT1 and their functional consequences. Pharmacogenetics. 2002;12:591–5.
Shikata E, Yamamoto R, Takane H, et al. Human organic cation transporter (OCT1 and OCT2) gene polymorphisms and therapeutic effects of metformin. J Hum Genet. 2007;52:117–22.
Emami Riedmaier A, Fisel P, Nies AT, et al. Metformin and cancer: from the pld medicine cabinet to pharmacological pitfalls and prospects. Trends Pharmacol Sci. 2013;34:126–35.
Shokri F, Ghaedi H, Fard SG, et al. Impact of ATM and SLC22A1 polymorphisms on therapeutic response to metformin in Iranian diabetic patients. Int J Mol Cell Med. 2016;5:1–7.
Dipanshu S. A Tale of Genetic Variation in the Human Slc22a1 Gene Encoding Oct1 Among Type 2 Diabetes Mellitus Population Groups of West Bengal, India. IMPACT Int J Res Applied, Nat Soc Sci. 2014;2:97–106.
Becker ML, Visser LE, Van Schaik RH, et al. Genetic variation in the organic cation transporter 1 is associated with metformin response in patients with diabetes mellitus. Pharmacogenomics J. 2009;9:242–7.
Chen L, Takizawa M, Chen E, et al. Genetic polymorphisms in the organic cation transporter 1 (OCT1) in Chinese and Japanese populations exhibit altered function. J Pharmacol Exp Ther. 2010;335:42–50.
Zhou Y, Ye W, Wang Y, et al. Genetic variants of OCT1 influence glycemic response to metformin in Han Chinese patients with type-2 diabetes mellitus in Shanghai. Int J Clin Exp Pathol. 2015;8:9533–42.