Abstract
Metformin is the most widely prescribed antidiabetic drug in the world. Despite its beneficial effects in reducing the risk for developing vascular complications associated with diabetes, the glycemic response to metformin is highly variable. Genetic factors, along with factors such as various comorbidities and body weight, contribute to this variability. In this chapter, we focus on genetic polymorphisms that associate with metformin pharmacokinetics as well as poor glycemic response to the drug. In particular, genetic polymorphisms in membrane transporters that play a role in metformin absorption, disposition, and response are highlighted. Studies in healthy volunteers, prediabetic and diabetic patients, and patients with polycystic ovary disease are described. Using genome-wide data, it is estimated that the heritability of glycemic response to metformin is around 30 %. The first genome-wide association study of metformin glycemic response in patients with type 2 diabetes reveals a locus in chromosome 11. Finally, we provide an overview of future directions for metformin pharmacogenomic studies to further elucidate genetic loci and targets for metformin action.
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Bailey CJ, Turner RC (1996) Metformin. N Engl J Med 334:574–579
Becker ML et al (2009) Genetic variation in the multidrug and toxin extrusion 1 transporter protein influences the glucose-lowering effect of metformin in patients with diabetes: a preliminary study. Diabetes 58:745–749
Becker ML, Pearson ER, Tkac I (2013) Pharmacogenetics of oral antidiabetic drugs. Int J Endocrinol 2013:686315
Berstein LM, Iyevleva AG, Vasilyev D, Poroshina TE, Imyanitov EN (2013) Genetic polymorphisms potentially associated with response to metformin in postmenopausal diabetics suffering and not suffering with cancer. Cell Cycle 12:3681–3688
Chen Y et al (2009) Effect of genetic variation in the organic cation transporter 2 on the renal elimination of metformin. Pharmacogenet Genomics 19:497–504
Chen L et al (2010) Role of organic cation transporter 3 (SLC22A3) and its missense variants in the pharmacologic action of metformin. Pharmacogenet Genomics 20:687–699
Cook MN, Girman CJ, Stein PP, Alexander CM (2007) 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 24:350–358
Ding Y et al (2014) The effect of lansoprazole, an OCT inhibitor, on metformin pharmacokinetics in healthy subjects. Eur J Clin Pharmacol 70:141–146
Florez JC et al (2012) The C allele of ATM rs11212617 does not associate with metformin response in the Diabetes Prevention Program. Diabetes Care 35:1864–1867
Gambineri A et al (2010) Organic cation transporter 1 polymorphisms predict the metabolic response to metformin in women with the polycystic ovary syndrome. J Clin Endocrinol Metab 95:E204–E208
Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL (1997) Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose–response trial. Am J Med 103:491–497
Giacomini KM et al (2010) Membrane transporters in drug development. Nat Rev Drug Discov 9:215–236
Graham GG et al (2011) Clinical pharmacokinetics of metformin. Clin Pharmacokinet 50:81–98
Grun B et al (2013) Trimethoprim-metformin interaction and its genetic modulation by OCT2 and MATE1 transporters. Br J Clin Pharmacol 76:787–796
GTEx Consortium (2013) The Genotype-Tissue Expression (GTEx) project. Nat Genet 45:580–585
Jablonski KA et al (2010) Common variants in 40 genes assessed for diabetes incidence and response to metformin and lifestyle intervention in the diabetes prevention program. Diabetes 59:2672–2681
Kahn SE et al (2006) Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 355:2427–2443
Kato Y et al (2010) Gene knockout and metabolome analysis of carnitine/organic cation transporter OCTN1. Pharm Res 27:832–840
Komatsu T et al (2011) Characterization of the human MATE2 proton-coupled polyspecific organic cation exporter. Int J Biochem Cell Biol 43:913–918
Kusuhara H et al (2011) Effects of a MATE protein inhibitor, pyrimethamine, on the renal elimination of metformin at oral microdose and at therapeutic dose in healthy subjects. Clin Pharmacol Ther 89:837–844
Masuda S et al (2006) Identification and functional characterization of a new human kidney-specific H+/organic cation antiporter, kidney-specific multidrug and toxin extrusion 2. J Am Soc Nephrol 17:2127–2135
Motohashi H et al (2013) Precise comparison of protein localization among OCT, OAT, and MATE in human kidney. J Pharm Sci 102:3302–3308
Nakamichi N et al (2013) Involvement of carnitine/organic cation transporter OCTN1/SLC22A4 in gastrointestinal absorption of metformin. J Pharm Sci 102:3407–3417
Nies AT et al (2009) Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver. Hepatology 50:1227–1240
Pau CT, Keefe C, Duran J, Welt C (2014) Metformin improves glucose effectiveness, not insulin sensitivity: predicting treatment response in women with polycystic ovary syndrome in an open-label, interventional study. J Clin Endocrinol Metab 99(5):1870–1878
Pernicova I, Korbonits M (2014) Metformin-mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol 10:143–156
Shu Y et al (2007) Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest 117:1422–1431
Sirtori CR et al (1978) Disposition of metformin (N, N-dimethylbiguanide) in man. Clin Pharmacol Ther 24:683–693
Stepensky D, Friedman M, Raz I, Hoffman A (2002) Pharmacokinetic-pharmacodynamic analysis of the glucose-lowering effect of metformin in diabetic rats reveals first-pass pharmacodynamic effect. Drug Metab Dispos 30:861–868
Stocker SL et al (2013) The effect of novel promoter variants in MATE1 and MATE2 on the pharmacokinetics and pharmacodynamics of metformin. Clin Pharmacol Ther 93:186–194
Tarasova L et al (2012) Association of genetic variation in the organic cation transporters OCT1, OCT2 and multidrug and toxin extrusion 1 transporter protein genes with the gastrointestinal side effects and lower BMI in metformin-treated type 2 diabetes patients. Pharmacogenet Genomics 22:659–666
Tkac I et al (2013) Pharmacogenomic association between a variant in SLC47A1 gene and therapeutic response to metformin in type 2 diabetes. Diabetes Obes Metab 15:189–191
Tucker GT et al (1981) Metformin kinetics in healthy subjects and in patients with diabetes mellitus. Br J Clin Pharmacol 12:235–246
van Leeuwen N et al (2012) 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 55:1971–1977
Viollet B, Foretz M (2013) Revisiting the mechanisms of metformin action in the liver. Ann Endocrinol (Paris) 74:123–129
Viollet B et al (2012) Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 122:253–270
Watanabe CK (1918) Studies in the metabolic changes induced by administration of guanidine bases. J Biol Chem 33:253
Woods A, Leiper JM, Carling D (2012) The role of ATM in response to metformin treatment and activation of AMPK. Nat Genet 44:360–361
Yang J, Lee SH, Goddard ME, Visscher PM (2011) GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet 88:76–82
Yee SW, Chen L, Giacomini KM (2012) The role of ATM in response to metformin treatment and activation of AMPK. Nat Genet 44:359–360
Yoon H, Cho HY, Yoo HD, Kim SM, Lee YB (2013) Influences of organic cation transporter polymorphisms on the population pharmacokinetics of metformin in healthy subjects. AAPS J 15:571–580
Zhang ZJ, Li S (2014) The prognostic value of metformin for cancer patients with concurrent diabetes: a systematic review and meta-analysis. Diabetes Obes Metab 16:707–710
Zhou M, Xia L, Wang J (2007) Metformin transport by a newly cloned proton-stimulated organic cation transporter (plasma membrane monoamine transporter) expressed in human intestine. Drug Metab Dispos 35:1956–1962
Zhou K et al (2009) Reduced-function SLC22A1 polymorphisms encoding organic cation transporter 1 and glycemic response to metformin: a GoDARTS study. Diabetes 58:1434–1439
Zhou K et al (2011) Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet 43:117–120
Zhou K et al (2014) Heritability of variation in glycaemic response to metformin: a genome-wide complex trait analysis. Lancet Diabetes Endocrinol 2(6):481–487
Zolk O (2012) Disposition of metformin: variability due to polymorphisms of organic cation transporters. Ann Med 44:119–129
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Yee, S.W., Zhou, K., Giacomini, K.M. (2016). Pharmacogenetics of Metformin. In: Florez, J. (eds) The Genetics of Type 2 Diabetes and Related Traits. Springer, Cham. https://doi.org/10.1007/978-3-319-01574-3_22
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DOI: https://doi.org/10.1007/978-3-319-01574-3_22
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