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 Article Swipe

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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 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 , V. Gudmundsdóttir , 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 ·

YOU? · · 2019 · Open Access · · DOI: https://doi.org/10.2337/dc18-2182

OBJECTIVE 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. RESEARCH DESIGN AND METHODS 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. RESULTS 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). CONCLUSIONS These results suggest that intestinal metformin transporters and concomitant medications play an important role in the gastrointestinal adverse effects of metformin.

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The Transporter Refueled

Concepts

Organic cation transport proteins Transporter Internal medicine Endocrinology Medicine Metformin Monoamine neurotransmitter Type 2 diabetes Diabetes mellitus Biochemistry Chemistry Receptor Serotonin Gene

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Type: article
Language: en
Landing Page: https://doi.org/10.2337/dc18-2182
PDF: https://care.diabetesjournals.org/content/diacare/42/6/1027.full.pdf
OA Status: bronze
Cited By: 59
References: 51
Related Works: 10
OpenAlex ID: https://openalex.org/W2895434434

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Title: 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

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Language: en

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Publication year: 2019

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Publication date: 2019-03-18

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Authors: 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 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, V. Gudmundsdóttir, 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

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Concepts: Organic cation transport proteins, Transporter, Internal medicine, Endocrinology, Medicine, Metformin, Monoamine neurotransmitter, Type 2 diabetes, Diabetes mellitus, Biochemistry, Chemistry, Receptor, Serotonin, Gene

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Cited by: 59

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