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
Year: 2019
Type: article
Study design: Observational Study
Abstract: Objectives 20-30% of patients with metformin treated type 2 diabetes experience gastrointestinal side effects leading to premature discontinuation in 5-10% of the cases. Gastrointestinal intolerance may reflect localised high concentrations of metformin in the gut. We hypothesized that reduced transport of metformin into the circulation via the plasma membrane monoamine transporter (PMAT) and organic cation transporter 1 (OCT1) could increase the risk of severe GI side effects. Research Design and Methods The study included 286 severe metformin intolerant and 1128 tolerant individuals from the IMI DIRECT consortium. We assessed the association of patient characteristics, concomitant medication and the burden of mutations in the SLC29A4 and SLC22A1 , genes that encode PMAT and OCT1, respectively, on odds of metformin intolerance using a logistic regression model. Results Women (p < 0.001) and older people (p < 0.001) were more likely to develop metformin intolerance. Concomitant use of metformin transporter inhibiting drugs increased the odds of intolerance by more than 70% (OR = 1.72 [1.26-2.32], p < 0.001). In a logistic regression model adjusted for age, sex, weight and population substructure, the G allele at rs3889348 ( SLC29A4 ) was associated with GI intolerance (OR = 1.34[1.09-1.65], p = 0.005). rs3889348 is the top cis-eQTL for SLC29A4 in gut tissue where carriers of the G allele had reduced expression. Homozygous carriers of the G allele treated with metformin transporter inhibiting drugs had over three times higher odds of intolerance compared to carriers of no G allele and not treated with inhibiting drugs (OR = 3.23 [1.71-6.39], p < 0.001). Using a genetic risk score (GRS) derived from SLC29A4 (rs3889348) and previously reported SLC22A1 variants (M420del, R61C, G401S), the odds of intolerance was more than twice in individuals who carry three or more risk alleles compared with those carrying none (OR = 2.15 [1.20-4.12], p = 0.01). Conclusions These results suggest that intestinal metformin transporters and concomitant medications play an important role in gastrointestinal side effects of metformin.
Source: Diabetes Care
DOI: 10.2337/dc18-2182
Authors: Adem Y. Dawed, Kaixin Zhou, Nienke van Leeuwen, Anubha Mahajan, Neil Robertson, Robert 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, C. Jennison, B. Ehrhardt, P. Baum, C. Schoelsch, J.I. Freijer, R. Grempler, U. Graefe-Mody, A.M. Hennige, C. Dings, T. Lehr, N. Scherer, I. Sihinecich, F. Pattou, V. Raverdi, R. Caiazzo, F. Torres, H. Verkindt, A. Mari, A. Tura, T. Giorgino, R. Bizzotto, P. Froguel, A. Bonneford, M. Canouil, V. Dhennin, C.A. Brorsson, S. Brunak, F. De Masi, V. Gudmundsdóttir, H.K. Pedersen, K. Banasik, E. Thomas, W. Sackett, H. Staerfeldt, A.T. Lundgaard, B. Nilsson, A.M. Nielsen, G. Mazzoni, T. Karaderi, S. Rasmussen, J. Johansen, R.L. Allesøe, A. Fritsche, B. Thorand, J. Adamski, H. Grallert, M. Haid, S. Sharma, M. Troll, J. Adam, J. Ferrer, P. Froguel, R.G. Eriksen, G. Frost, R. Haussler, M.-G. Hong, J.M. Schwenk, M. Uhlen, C. Nicolay, I. Pavo, B. Steckel-Hamann, M.K. Thomas, K. Adragni, H. Wu, L.M. 't Hart, R.C. Roderick, N. van Leeuwen, K.F. Dekkers, F. Frau, J. Gassenhuber, B. Jablonka, P. Musholt, H. Ruetten, J. Tillner, T. Baltauss, O. Bernard, N. Poenaru, M. de Preville, M. Rodriquez, K.H. Arumugam, L. Allin, T. Engelbrechtsen, T.H. Hansen, A. Hansen, A. Forman, O. Jonsson, A. Pedersen, J.K. Dutta, H. Vogt, M. Vestergaard, T. Laakso, T. Kokkola, P.W. Kuulasmaa, G.N. Franks, H. Giordano, H. Pomares-Millan, P. Fitipaldi, M. Mutie, M. Klintenberg, L. Bergstrom, M. Groop, N. Ridderstrale, H.A. Atabaki Pasdar, A.J. Deshmukh, D. Heggie, D. Wake, I. McEvoy, M. McVittie, A.T. Walker, A.V. Hattersley, A.G. Hill, T.J. Jones, M.H. McDonald, R. Perry, M. Nice, C.E. Hudson, E.T. Thorne, A. Dermitzakis, L. Viñuela, H. Cabrelli, A.Y. Loftus, L. Dawed, I.M. Donnelly, E.R. Forgie, C.N. Pearson, A.A. Palmer, R.W. Brown, A. Koivula, M. Wesolowska-Andersen, N. Abdalla, J. McRobert, J. Fernandez, M. Kaye, A. Mourby, M.I. Mahajan, N. McCarthy, H. Shah, Y. Teare, N. Jiao, S. Robertson, R.W. Gough, A.D. Holl, F. Koopman, J.W. Rutters, L. Beulens, A.D. Groeneveld, J.D. Koopman, E.L. Bell, Thomas, B. Whitcher
Institutions: University of Dundee, Leiden University Medical Center, Centre for Human Genetics, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Lund University, Skåne University Hospital, Amsterdam Public Health, Amsterdam University Medical Centers, University of Exeter, Universität Ulm, German Center for Diabetes Research, Federal Institute for Drugs and Medical Devices, Harvard University, Umeå University, National Institute for Health and Care Research, Oxford University Hospitals NHS Trust
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: bronze
Awards: G1073258374, G119964413, DIabetes REsearCh on patient sTratification, G1714855358, G1732308444, G3207356259, G3529949959, G393177772, G5702163051, Stratified medicine in Type 2 diabetes: Insights from the study of drug response., Stratified medicine in Type 2 diabetes: Insights from the study of drug response., Integrating clinical features and biomarkers to improve diabetes classification and treatment in young adults
OpenAlex ID: W2895434434