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Variation in the Plasma Membrane Monoamine Transporter (PMAT) (Encoded by SLC29A4 ) and Organic Cation Transporter 1 (OCT1) (Encoded by SLC22A1 ) and Gastrointestinal Intolerance to Metformin in Type 2 Diabetes: An IMI DIRECT Study

2019; American Diabetes Association; Volume: 42; Issue: 6 Linguagem: Inglês

10.2337/dc18-2182

1935-5548

Adem Y. Dawed, Kaixin Zhou, Nienke van Leeuwen, Anubha Mahajan, Neil Robertson, Robert W. Koivula, Petra J. M. Elders, Simone P. Rauh, Angus G. Jones, Reinhard W. Holl, Julia C. Stingl, Paul W. Franks, Mark I. McCarthy, Leen M. ‘t Hart, Ewan R. Pearson, Christopher Jennison, Beate Ehrhardt, Patrick Baum, Corinna Schoelsch, Jan Freijer, Rolf Grempler, Ulrike Graefe‐Mody, Anita M. Hennige, Christiane Dings, Thorsten Lehr, N. Scherer, Iryna Sihinecich, François Pattou, V. Raverdi, Robert Caïazzo, F. Torres, Hélène Verkindt, Andrea Mari, Andrea Tura, Toni Giorgino, Roberto Bizzotto, Philippe Froguel, Amelie Bonneford, Mickaël Canouil, Véronique Dhennin, Caroline Brorsson, Søren Brunak, Francesco De Masi, Vilborg Guðmundsdóttir, Hans Kristian Pedersen, K. Banasik, E. S. Thomas, Walter G. Sackett, Hans‐Henrik Stærfeldt, Agnete Troen Lundgaard, Birgitte Nilsson, Nielsen Am, Gianluca Mazzoni, Tugce Karaderi, Simon Rasmussen, Joachim Johansen, Rosa Lundbye Allesøe, A. Fritsche, Barbara Thorand, Jerzy Adamski, H. Grallert, Mark Haid, Sapna Sharma, Mark Troll, Jean‐Michel Adam, Jorge Ferrer, Philippe Froguel, R.G. Eriksen, Gary Frost, Ragna S. Häussler, Mun‐Gwan Hong, Jochen M. Schwenk, Mathias Uhlén, CLAUDIA NICOLAY, Imre Pávó, Birgit Steckel-Hamann, Melissa K. Thomas, Kofi P. Adragni, Huihai Wu, Leen M. ‘t Hart, Ryland Roderick, Nienke van Leeuwen, Koen F. Dekkers, Francesca Frau, Johann Gassenhuber, Bernd Jablonka, PB Musholt, Hartmut Ruetten, J. Tillner, Tania Baltauss, Olivier Bernard, N. Poenaru, Michel Préville, M. Rodriquez, Kumar Arumugam, Leslie Allin, T. Engelbrechtsen, Tue H. Hansen, Anne-Louise S. Hansen, Axel Forman, Olof Jonsson, Anette Fischer Pedersen, JK Dutta, H.‐J. Vogt, Mogens Vestergaard, Teemu Laakso, Tarja Kokkola, P.W. Kuulasmaa, G.N. Franks, Heidi Giordano, Hugo Pomares‐Millan, P. Fitipaldi, M. Mutie, Maria Klintenberg, Lea Bergström, M. Groop, N. Ridderstrale, Homayoon Pasdar, Abhishek Deshmukh, D. Heggie, Deborah J. Wake, I. McEvoy, M. McVittie, A.T. Walker, Andrew T. Hattersley, Andrew G. Hill, T.J. Jones, Timothy J. McDonald, Roger R Perry, Marvin Nice, Charles E. Hudson, E. Tom Thorne, A. Dermitzakis, Laura Viñuela, H. Cabrelli, Alison Loftus, L. Dawed, Iona Donnelly, E.R. Forgie, C.N. Pearson, A.A. Palmer, R. W. Brown, Anu Koivula, M. Wesolowska-Andersen, Nabil Abdalla, J. McRobert, J. Fernandez, Michael Kaye, A. Mourby, M.I. Mahajan, Nina S. McCarthy, Hetal Shah, Y. Teare, Ning Jiao, S. Robertson, Rachel Gough, A.D. Holl, Frieda A. Koopman, J.W. Rutters, L. Beulens, A.D. Groeneveld, J.D. Koopman, Eric L. Bell, Thomas, Brandon Whitcher,

Pancreatic function and diabetes

Gastrointestinal adverse effects occur in 20-30% of patients with metformin-treated type 2 diabetes, leading to premature discontinuation in 5-10% of the cases. Gastrointestinal intolerance may reflect localized high concentrations of metformin in the gut. We hypothesized that reduced transport of metformin via the plasma membrane monoamine transporter (PMAT) and organic cation transporter 1 (OCT1) could increase the risk of severe gastrointestinal adverse effects.The study included 286 severe metformin-intolerant and 1,128 metformin-tolerant individuals from the IMI DIRECT (Innovative Medicines Initiative: DIabetes REsearCh on patient straTification) consortium. We assessed the association of patient characteristics, concomitant medication, and the burden of mutations in the SLC29A4 and SLC22A1 genes on odds of intolerance.Women (P < 0.001) and older people (P < 0.001) were more likely to develop metformin intolerance. Concomitant use of transporter-inhibiting drugs increased the odds of intolerance (odds ratio [OR] 1.72, P < 0.001). In an adjusted logistic regression model, the G allele at rs3889348 (SLC29A4) was associated with gastrointestinal intolerance (OR 1.34, P = 0.005). rs3889348 is the top cis-expression quantitative trait locus for SLC29A4 in gut tissue where carriers of the G allele had reduced expression. Homozygous carriers of the G allele treated with transporter-inhibiting drugs had more than three times higher odds of intolerance compared with carriers of no G allele and not treated with inhibiting drugs (OR 3.23, P < 0.001). Use of a genetic risk score derived from rs3889348 and SLC22A1 variants found that the odds of intolerance were more than twice as high in individuals who carry three or more risk alleles compared with those carrying none (OR 2.15, P = 0.01).These results suggest that intestinal metformin transporters and concomitant medications play an important role in the gastrointestinal adverse effects of metformin.