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
Author:
Dawed Adem Y.1ORCID, Zhou Kaixin1, van Leeuwen Nienke2, Mahajan Anubha3, Robertson Neil34, Koivula Robert45, Elders Petra J.M.6, Rauh Simone P.7, Jones Angus G.8, Holl Reinhard W.9, Stingl Julia C.10, Franks Paul W.51112ORCID, McCarthy Mark I.3413, ‘t Hart Leen M.2714, Pearson Ewan R.1ORCID, Jennison C., Ehrhardt B., Baum P., Schoelsch C., Freijer J.I., Grempler R., Graefe-Mody U., Hennige A.M., Dings C., Lehr T., Scherer N., Sihinecich I., Pattou F., Raverdi V., Caiazzo R., Torres F., Verkindt H., Mari A., Tura A., Giorgino T., Bizzotto R., Froguel P., Bonneford A., Canouil M., Dhennin V., Brorsson C.A., Brunak S., De Masi F., Gudmundsdóttir V., Pedersen H.K., Banasik K., Thomas E., Sackett W., Staerfeldt H., Lundgaard A.T., Nilsson B., Nielsen A.M., Mazzoni G., Karaderi T., Rasmussen S., Johansen J., Allesøe R.L., Fritsche A., Thorand B., Adamski J., Grallert H., Haid M., Sharma S., Troll M., Adam J., Ferrer J., Froguel P., Eriksen R.G., Frost G., Haussler R., Hong M.-G., Schwenk J.M., Uhlen M., Nicolay C., Pavo I., Steckel-Hamann B., Thomas M.K., Adragni K., Wu H., 't Hart L.M., Roderick R.C., van Leeuwen N., Dekkers K.F., Frau F., Gassenhuber J., Jablonka B., Musholt P., Ruetten H., Tillner J., Baltauss T., Bernard O., Poenaru N., de Preville M., Rodriquez M., Arumugam K.H., Allin L., Engelbrechtsen T., Hansen T.H., Hansen A., Forman A., Jonsson O., Pedersen A., Dutta J.K., Vogt H., Vestergaard M., Laakso T., Kokkola T., Kuulasmaa P.W., Franks G.N., Giordano H., Pomares-Millan H., Fitipaldi P., Mutie M., Klintenberg M., Bergstrom L., Groop M., Ridderstrale N., Atabaki Pasdar H.A., Deshmukh A.J., Heggie D., Wake D., McEvoy I., McVittie M., Walker A.T., Hattersley A.V., Hill A.G., Jones T.J., McDonald M.H., Perry R., Nice M., Hudson C.E., Thorne E.T., Dermitzakis A., Viñuela L., Cabrelli H., Loftus A.Y., Dawed L., Donnelly I.M., Forgie E.R., Pearson C.N., Palmer A.A., Brown R.W., Koivula A., Wesolowska-Andersen M., Abdalla N., McRobert J., Fernandez J., Kaye M., Mourby A., Mahajan M.I., McCarthy N., Shah H., Teare Y., Jiao N., Robertson S., Gough R.W., Holl A.D., Koopman F., Rutters J.W., Beulens L., Groeneveld A.D., Koopman J.D., Bell E.L., Thomas , Whitcher B.,
Affiliation:
1. Division of Population Health and Genomics, School of Medicine, University of Dundee, Dundee, U.K. 2. Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands 3. Wellcome Centre for Human Genetics, University of Oxford, Oxford, U.K. 4. Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K. 5. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Skåne University Hospital, Malmö, Lund University, Malmö, Sweden 6. Department of General Practice and Elderly Care Medicine, Amsterdam Public Health Research Institute, Amsterdam University Medical Center, Amsterdam, the Netherlands 7. Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, Amsterdam University Medical Center, Amsterdam, the Netherlands 8. Institute of Clinical and Biological Sciences, University of Exeter Medical School, Exeter, U.K. 9. Institute of Epidemiology and Medical Biometry (ZIBMT), University of Ulm, Ulm, Germany, and German Center for Diabetes Research (DZD), München-Neuherberg, Germany 10. Research Division, Federal Institute for Drugs and Medical Devices, Bonn, Germany 11. Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden 12. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 13. Oxford National Institute for Health Research Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, U.K. 14. Section of Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands
Abstract
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.
Publisher
American Diabetes Association
Subject
Advanced and Specialized Nursing,Endocrinology, Diabetes and Metabolism,Internal Medicine
Cited by
44 articles.
订阅此论文施引文献
订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献
|
|