Intronic Variants in OCT1 are Associated with All-Cause and Cardiovascular Mortality in Metformin Users with Type 2 Diabetes

References

• Mendis S, Armstrong T, Bettcher D, et al. Global Status Report on Noncommunicable Diseases 2014. World Health Organisation. 2014. ISBN 9789241564854.
   Google Scholar
• Martín-Timón I. Type 2 diabetes and cardiovascular disease: have all risk factors the same strength? World J Diabetes. 2014;5(4):444. doi:10.4239/wjd.v5.i4.444
   PubMedGoogle Scholar
• Gu K, Cowie CC, Harris MI. Diabetes and decline in heart disease mortality in US adults. J Am Med Assoc. 1999;281(14):1291–1297. doi:10.1001/jama.281.14.1291
   PubMed Web of Science ®Google Scholar
• Diabetes Drafting Group. Prevalence of small vessel and large vessel disease in diabetic patients from 14 centres - the World Health Organisation multinational study of vascular disease in diabetics. Diabetologia. 1985;28(8):615–640. doi:10.1007/BF00290267
   PubMedGoogle Scholar
• Griffin SJ, Leaver JK, Irving GJ. Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia. 2017;60(9):1620–1629. doi:10.1007/s00125-017-4337-9
   PubMed Web of Science ®Google Scholar
• El-Mir MY, Nogueira V, Fontaine E, Avéret N, Rigoulet M, Leverve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem. 2000;275(1):223–228. doi:10.1074/jbc.275.1.223
   PubMed Web of Science ®Google Scholar
• Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000;348(3):607–614. doi:10.1042/0264-6021:3480607
   PubMed Web of Science ®Google Scholar
• Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature. 2013;494(7436):256–260. doi:10.1038/nature11808
   PubMed Web of Science ®Google Scholar
• Fullerton MD, Galic S, Marcinko K, et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat Med. 2013;19(12):1649–1654. doi:10.1038/nm.3372
   PubMed Web of Science ®Google Scholar
• Madiraju AK, Erion DM, Rahimi Y, et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature. 2014;510(7506):542–546. doi:10.1038/nature13270
   PubMed Web of Science ®Google Scholar
• Prattichizzo F, Giuliani A, Mensa E, et al. Pleiotropic effects of metformin: shaping the microbiome to manage type 2 diabetes and postpone ageing. Ageing Res Rev. 2018;48:87–98. doi:10.1016/j.arr.2018.10.003
   PubMedGoogle Scholar
• Fiorentino TV, Suraci E, Arcidiacono GP, et al. Duodenal sodium/glucose cotransporter 1 expression under fasting conditions is associated with postload hyperglycemia. J Clin Endocrinol Metab. 2017;102(11):3979–3989. doi:10.1210/jc.2017-00348
   PubMedGoogle Scholar
• Bauer PV, Duca FA, Waise TMZ, et al. Metformin alters upper small intestinal microbiota that impact a glucose-SGLT1-sensing glucoregulatory pathway. Cell Metab. 2018;27(1):101–117.e5. doi:10.1016/j.cmet.2017.09.019
   PubMed Web of Science ®Google Scholar
• Gorboulev V, Rehman S, Albert CM, et al. Assay conditions influence affinities of rat organic cation transporter 1: analysis of mutagenesis in the modeled outward-facing cleft by measuring effects of substrates and inhibitors on initial uptake. Mol Pharmacol. 2018;93(4):402–415. doi:10.1124/mol.117.110767
   PubMed Web of Science ®Google Scholar
• Papanas N, Maltezos E, Mikhailidis DP. Metformin: diamonds are forever. Expert Opin Pharmacother. 2009;10(15):2395–2397. doi:10.1517/14656560903176453
   PubMed Web of Science ®Google Scholar
• Heckman-Stoddard BM, DeCensi A, Sahasrabuddhe VV, Ford LG. Repurposing metformin for the prevention of cancer and cancer recurrence. Diabetologia. 2017;60(9):1639–1647. doi:10.1007/s00125-017-4372-6
   PubMed Web of Science ®Google Scholar
• Romero R, Erez O, Hüttemann M, et al. Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity. Am J Obstet Gynecol. 2017;217(3):282–302. doi:10.1016/j.ajog.2017.06.003
   PubMed Web of Science ®Google Scholar
• Valencia WM, Palacio A, Tamariz L, Florez H. Metformin and ageing: improving ageing outcomes beyond glycaemic control. Diabetologia. 2017;60(9):1630–1638. doi:10.1007/s00125-017-4349-5
   PubMed Web of Science ®Google Scholar
• Sakata T, Anzai N, Kimura T, et al. Functional analysis of human organic cation transporter OCT3 (SLC22A3) polymorphisms. J Pharmacol Sci. 2010;113(3):263–266. doi:10.1254/jphs.09331SC
   PubMedGoogle Scholar
• Wang DS, Jonker JW, Kato Y, Kusuhara H, Schinkel AH, Sugiyama Y. Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J Pharmacol Exp Ther. 2002;302(2):510–515. doi:10.1124/jpet.102.034140
   PubMed Web of Science ®Google Scholar
• Dujic T, Causevic A, Bego T, et al. Organic cation transporter 1 variants and gastrointestinal side effects of metformin in patients with type 2 diabetes. Diabet Med. 2016;33(4):511–514. doi:10.1111/dme.13040
   PubMed Web of Science ®Google Scholar
• Christensen MMH, Brasch-Andersen C, Green H, et al. The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c. Pharmacogenet Genomics. 2011;21(12):837–850. doi:10.1097/FPC.0b013e32834c0010
   PubMed Web of Science ®Google Scholar
• Tzvetkov MV, Vormfelde SV, Balen D, et al. The effects of genetic polymorphisms in the organic cation transporters OCT1, OCT2, and OCT3 on the renal clearance of metformin. Clin Pharmacol Ther. 2009;86(3):299–306. doi:10.1038/clpt.2009.92
   PubMed Web of Science ®Google Scholar
• Becker ML, Visser LE, Van Schaik RHN, Hofman A, Uitterlinden AG, Stricker BHC. Interaction between polymorphisms in the OCT1 and MATE1 transporter and metformin response. Pharmacogenet Genomics. 2010;20(1):38–44. doi:10.1097/FPC.0b013e328333bb11
   PubMed Web of Science ®Google Scholar
• Bradfield JP, Qu HQ, Wang K, et al. A genome-wide meta-analysis of six type 1 diabetes cohorts identifies multiple associated loci. PLoS Genet. 2011;7(9):e1002293. doi:10.1371/journal.pgen.1002293
   PubMed Web of Science ®Google Scholar
• Saxena R, Voight BF, Lyssenko V, et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science. 2007;316(5829):1331–1336. doi:10.1126/science.1142358
   PubMed Web of Science ®Google Scholar
• Goswami S, Yee SW, Stocker S, et al. Genetic variants in transcription factors are associated with the pharmacokinetics and pharmacodynamics of metformin. Clin Pharmacol Ther. 2014;96(3):370–379. doi:10.1038/clpt.2014.109
   PubMed Web of Science ®Google Scholar
• Reitman ML, Schadt EE. Pharmacogenetics of metformin response: a step in the path toward personalized medicine. J Clin Invest. 2007;117(5):1226–1229. doi:10.1172/JCI32133
   PubMedGoogle Scholar
• 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(2):117–122. doi:10.1007/s10038-006-0087-0
   PubMed Web of Science ®Google Scholar
• 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(5):1422–1431. doi:10.1172/JCI30558
   PubMed Web of Science ®Google Scholar
• Zhou K, Donnelly LA, Kimber CH, et al. Reduced-function SLC22A1 polymorphisms encoding organic cation transporter 1 and glycemic response to metformin: a GoDARTS study. Diabetes. 2009;58(6):1434–1439. doi:10.2337/db08-0896
   PubMed Web of Science ®Google Scholar
• Becker ML, Visser LE, van Schaik RHN, Hofman A, Uitterlinden AG, Stricker BHC. Genetic variation in the organic cation transporter 1 is associated with metformin response in patients with diabetes mellitus. Pharmacogenomics J. 2009;9(4):242–247. doi:10.1038/tpj.2009.15
   PubMed Web of Science ®Google Scholar
• Dujic T, Zhou K, Yee SW, et al. Variants in pharmacokinetic transporters and glycemic response to metformin: a metgen meta-analysis. Clin Pharmacol Ther. 2017;101(6):763–772. doi:10.1002/cpt.567
   PubMed Web of Science ®Google Scholar
• Schweighofer N, Lerchbaum E, Trummer O, Schwetz V, Pieber T, Obermayer-Pietsch B. Metformin resistance alleles in polycystic ovary syndrome: pattern and association with glucose metabolism. Pharmacogenomics. 2014;15(3):305–317. doi:10.2217/pgs.13.223
   PubMed Web of Science ®Google Scholar
• Winkelmann BR, März W, Boehm BO, et al. Rationale and design of the LURIC study - a resource for functional genomics, pharmacogenomics and long-term prognosis of cardiovascular disease. Pharmacogenomics. 2001;2(1 SUPPL. 1):S1–S73. doi:10.1517/14622416.2.1.S1
   PubMedGoogle Scholar
• Pilz S, März W, Wellnitz B, et al. Association of vitamin D deficiency with heart failure and sudden cardiac death in a large cross-sectional study of patients referred for coronary angiography. J Clin Endocrinol Metab. 2008;93(10):3927–3935. doi:10.1210/jc.2008-0784
   PubMed Web of Science ®Google Scholar
• Thomas GN, Hartaigh BÓ, Bosch JA, et al. Vitamin D levels predict all-cause and cardiovascular disease mortality in subjects with the metabolic syndrome: the Ludwigshafen Risk and Cardiovascular health (LURIC) study. Diabetes Care. 2012;35(5):1158–1164. doi:10.2337/dc11-1714
   PubMed Web of Science ®Google Scholar
• Brandenburg VM, Kleber ME, Vervloet MG, et al. Fibroblast growth factor 23 (FGF23) and mortality: the Ludwigshafen risk and cardiovascular health study. Atherosclerosis. 2014;237(1):53–59. doi:10.1016/j.atherosclerosis.2014.08.037
   PubMed Web of Science ®Google Scholar
• Inker LA, Schmid CH, Tighiouart H, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med. 2012;367(1):20–29. doi:10.1056/NEJMoa1114248
   PubMed Web of Science ®Google Scholar
• American Diabetes Association. Summary of revisions to the 2011 clinical practice recommendations. Diabetes Care. 2011;34(Suppl 1).
   Google Scholar
• O’Hartaigh B, Neil Thomas G, Silbernagel G, et al. Association of 25-hydroxyvitamin D with type 2 diabetes among patients undergoing coronary angiography: cross-sectional findings from the LUdwigshafen Risk and Cardiovascular Health (LURIC) study. Clin Endocrinol (Oxf). 2013;79(2):192–198. doi:10.1111/cen.12024
   PubMedGoogle Scholar
• Ward LD, Kellis M. HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease. Nucleic Acids Res. 2016;44(D1):D877–D881. doi:10.1093/nar/gkv1340
   PubMed Web of Science ®Google Scholar
• Ward LD, Kellis M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 2012;40(D1):D930–D934. doi:10.1093/nar/gkr917
   PubMed Web of Science ®Google Scholar
• Friedrich T, Scheide D. The respiratory complex I of bacteria, archaea and eukarya and its module common with membrane-bound multisubunit hydrogenases. FEBS Lett. 2000;479(1–2):1–5. doi:10.1016/s0014-5793(00)01867-6
   PubMedGoogle Scholar
• Chelakkot C, Choi Y, Kim DK, et al. Akkermansia muciniphila-derived extracellular vesicles influence gut permeability through the regulation of tight junctions. Exp Mol Med. 2018;50(2):e450–11. doi:10.1038/emm.2017.282
   PubMed Web of Science ®Google Scholar
• Beaumont M, Neyrinck AM, Olivares M, et al. The gut microbiota metabolite indole alleviates liver inflammation in mice. FASEB J Off Publ Fed Am Soc Exp Biol. 2018:fj201800544. doi:10.1096/fj.201800544.
   Google Scholar
• Wang X, He G, Peng Y, Zhong W, Wang Y, Zhang B. Sodium butyrate alleviates adipocyte inflammation by inhibiting NLRP3 pathway. Sci Rep. 2015;5(1):12676. doi:10.1038/srep12676
   PubMedGoogle Scholar
• Vinolo MAR, Rodrigues HG, Nachbar RT, Curi R. Regulation of inflammation by short chain fatty acids. Nutrients. 2011;3(10):858–876. doi:10.3390/nu3100858
   PubMed Web of Science ®Google Scholar
• Turgan N, Ersöz B, Çoker C, Hamulu F, Yilmaz C, Elmaci S. Glucose metabolism and catecholamine responses during physical exercise in non-insulin-dependent diabetes. Clin Chem Lab Med. 1996;34(9):683–690. doi:10.1515/cclm.1996.34.9.683
   Google Scholar
• Guigas B, de Leeuw van Weenen JE, van Leeuwen N, et al. Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and type 2 diabetes susceptibility. Diabet Med. 2014;31(8):1001–1008. doi:10.1111/dme.12464
   PubMedGoogle Scholar
• Straznicky NE, Grima MT, Lambert EA, et al. Arterial norepinephrine concentration is inversely and independently associated with insulin clearance in obese individuals with metabolic syndrome. J Clin Endocrinol Metab. 2015;100(4):1544–1550. doi:10.1210/jc.2014-3796
   PubMedGoogle Scholar
• Pellinger TK, Dumke BR, Halliwill JR. Effect of H1- and H2-histamine receptor blockade on postexercise insulin sensitivity. Physiol Rep. 2013;1(2). doi:10.1002/phy2.33
   PubMedGoogle Scholar
• Kim K, Oh CM, Ohara-Imaizumi M, et al. Functional role of serotonin in insulin secretion in a diet-induced insulin-resistant state. Endocrinology. 2015;156(2):444–452. doi:10.1210/en.2014-1687
   PubMedGoogle Scholar
• Ilcol YO, Cansev M, Yilmaz MS, Hamurtekin E, Ulus IH. Peripheral administration of CDP-choline and its cholinergic metabolites increases serum insulin: muscarinic and nicotinic acetylcholine receptors are both involved in their actions. Neurosci Lett. 2008;431(1):71–76. doi:10.1016/j.neulet.2007.11.024
   PubMedGoogle Scholar
• Pienaar PR, Micklesfield LK, Levitt NS, et al. Insulin resistance is associated with lower acetylcholine-induced microvascular reactivity in nondiabetic women. Metab Syndr Relat Disord. 2014;12(3):178–184. doi:10.1089/met.2013.0126
   PubMedGoogle Scholar
• Sala-Rabanal M, Li DC, Dake GR, et al. Polyamine transport by the polyspecific organic cation transporters OCT1, OCT2, and OCT3. Mol Pharm. 2013;10(4):1450–1458. doi:10.1021/mp400024d
   PubMedGoogle Scholar
• Lin Y, Zhang X, Wang L, et al. Polyamine depletion attenuates isoproterenol-induced hypertrophy and endoplasmic reticulum stress in cardiomyocytes. Cell Physiol Biochem. 2014;34(5):1455–1465. doi:10.1159/000366350
   PubMedGoogle Scholar
• Mastracci TL, Robertson MA, Mirmira RG, Anderson RM. Polyamine biosynthesis is critical for growth and differentiation of the pancreas. Sci Rep. 2015;5(1). doi:10.1038/srep13269
   Google Scholar
• Suzuki J, Ogawa M, Watanabe R, et al. Roles of prostaglandin E2 in cardiovascular diseases. Int Heart J. 2011;52(5):266–269. doi:10.1536/ihj.52.266
   PubMed Web of Science ®Google Scholar
• Docanto MM, Ham S, Corbould A, Brown KA. Obesity-associated inflammatory cytokines and prostaglandin E2 stimulate glucose transporter mRNA expression and glucose uptake in primary human adipose stromal cells. J Interf Cytokine Res. 2015;35(8):600–605. doi:10.1089/jir.2014.0194
   PubMed Web of Science ®Google Scholar
• Nakhjavani M, Ghazizadeh Z, Aghajaninargesi A, et al. Prostaglandin F2 alpha plasma concentration predicts glycemic control and oxidation status in patients with type 2 diabetes mellitus. Clin Lab. 2014;60(12):2073–2080. doi:10.7754/Clin.Lab.2014.140405
   PubMedGoogle Scholar
• Liang X, Yee SW, Chien HC, et al. Organic cation transporter 1 (OCT1) modulates multiple cardiometabolic traits through effects on hepatic thiamine content. PLoS Biol. 2018;16(4):e2002907. doi:10.1371/journal.pbio.2002907
   PubMed Web of Science ®Google Scholar
• He L, Wondisford FE. Metformin action: concentrations matter. Cell Metab. 2015;21(2):159–162. doi:10.1016/j.cmet.2015.01.003
   PubMed Web of Science ®Google Scholar
• Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017;60(9):1577–1585. doi:10.1007/s00125-017-4342-z
   PubMed Web of Science ®Google Scholar
• Lizcano JM, Göransson O, Toth R, et al. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J. 2004;23(4):833–843. doi:10.1038/sj.emboj.7600110
   PubMed Web of Science ®Google Scholar
• Krishan S, Richardson DR, Sahni S. Adenosine monophosphate -activated kinase and its key role in catabolism: structure, regulation, biological activity, and pharmacological activation. Mol Pharmacol. 2015;87(3):363–377. doi:10.1124/mol.114.095810
   PubMedGoogle Scholar
• Tian C, Fang S, Du X, Jia C. Association of the C47T polymorphism in SOD2 with diabetes mellitus and diabetic microvascular complications: a meta-analysis. Diabetologia. 2011;54(4):803–811. doi:10.1007/s00125-010-2004-5
   PubMed Web of Science ®Google Scholar