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Variation in the pl...
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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- Dawed, Adem Y. (author)
- Ninewells Hospital and Medical School
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- Zhou, Kaixin (author)
- Ninewells Hospital and Medical School
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- van Leeuwen, Nienke (author)
- Leiden University Medical Centre
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- Mahajan, Anubha (author)
- Wellcome Trust Centre for Human Genetics
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- Robertson, Neil (author)
- University of Oxford
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- Koivula, Robert (author)
- Lund University,Lunds universitet,Genetisk och molekylär epidemiologi,Forskargrupper vid Lunds universitet,Genetic and Molecular Epidemiology,Lund University Research Groups,Skåne University Hospital
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- Elders, Petra J.M. (author)
- Academic Medical Center of University of Amsterdam (AMC)
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- Rauh, Simone P. (author)
- Academic Medical Center of University of Amsterdam (AMC)
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- Jones, Angus G. (author)
- University of Exeter
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- Holl, Reinhard W. (author)
- University of Ulm
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- Stingl, Julia C. (author)
- German Federal Institute for Drugs and Medical Devices
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- Franks, Paul W. (author)
- Umeå universitet,Umeå University,Lund University,Lunds universitet,Genetisk och molekylär epidemiologi,Forskargrupper vid Lunds universitet,Genetic and Molecular Epidemiology,Lund University Research Groups,Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Skåne University Hospital, Malmö, Lund University, Malmö, Sweden; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA,Harvard University,Avdelningen för medicin
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- McCarthy, Mark I. (author)
- Wellcome Trust Centre for Human Genetics,University of Oxford
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- t Hart, Leen M. (author)
- Leiden University Medical Centre
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- Pearson, Ewan R. (author)
- Ninewells Hospital and Medical School
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(creator_code:org_t)
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- 2019-03-18
- 2019
- English 7 s.
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In: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 42:6, s. 1027-1033
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http://dx.doi.org/10...
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https://care.diabete...
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https://lup.lub.lu.s...
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https://doi.org/10.2...
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Dawed, Adem Y.
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Zhou, Kaixin
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van Leeuwen, Nie ...
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Mahajan, Anubha
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Robertson, Neil
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Koivula, Robert
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show more...
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Elders, Petra J. ...
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Rauh, Simone P.
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Jones, Angus G.
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Holl, Reinhard W ...
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Stingl, Julia C.
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Franks, Paul W.
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McCarthy, Mark I ...
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t Hart, Leen M.
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Pearson, Ewan R.
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Endocrinology an ...
- Articles in the publication
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Diabetes Care
- By the university
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Lund University
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Umeå University