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

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, IMI DIRECT Consortium

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Pages (from-to)1027-1033
JournalDiabetes Care
Volume42
Issue number6
DOIs
Publication statusPublished - 1 Jun 2019

Cite this

Dawed, Adem Y. ; Zhou, Kaixin ; van Leeuwen, Nienke ; Mahajan, Anubha ; Robertson, Neil ; Koivula, Robert ; Elders, Petra J. M. ; Rauh, Simone P. ; Jones, Angus G. ; Holl, Reinhard W. ; Stingl, Julia C. ; Franks, Paul W. ; McCarthy, Mark I. ; t Hart, Leen M. ; Pearson, Ewan R. ; IMI DIRECT Consortium. / 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. In: Diabetes Care. 2019 ; Vol. 42, No. 6. pp. 1027-1033.
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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",
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.",
author = "Dawed, {Adem Y.} and Kaixin Zhou and {van Leeuwen}, Nienke and Anubha Mahajan and Neil Robertson and Robert Koivula and Elders, {Petra J. M.} and Rauh, {Simone P.} and Jones, {Angus G.} and Holl, {Reinhard W.} and Stingl, {Julia C.} and Franks, {Paul W.} and McCarthy, {Mark I.} and {t Hart}, {Leen M.} and Pearson, {Ewan R.} and {IMI DIRECT Consortium}",
year = "2019",
month = "6",
day = "1",
doi = "10.2337/dc18-2182",
language = "English",
volume = "42",
pages = "1027--1033",
journal = "Diabetes Care",
issn = "0149-5992",
publisher = "American Diabetes Association Inc.",
number = "6",

}

Dawed, AY, Zhou, K, van Leeuwen, N, Mahajan, A, Robertson, N, Koivula, R, Elders, PJM, Rauh, SP, Jones, AG, Holl, RW, Stingl, JC, Franks, PW, McCarthy, MI, t Hart, LM, Pearson, ER & IMI DIRECT Consortium 2019, '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' Diabetes Care, vol. 42, no. 6, pp. 1027-1033. https://doi.org/10.2337/dc18-2182

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. / Dawed, Adem Y.; Zhou, Kaixin; van Leeuwen, Nienke; Mahajan, Anubha; Robertson, Neil; Koivula, Robert; Elders, Petra J. M.; Rauh, Simone P.; Jones, Angus G.; Holl, Reinhard W.; Stingl, Julia C.; Franks, Paul W.; McCarthy, Mark I.; t Hart, Leen M.; Pearson, Ewan R.; IMI DIRECT Consortium.

In: Diabetes Care, Vol. 42, No. 6, 01.06.2019, p. 1027-1033.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - 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

AU - Dawed, Adem Y.

AU - Zhou, Kaixin

AU - van Leeuwen, Nienke

AU - Mahajan, Anubha

AU - Robertson, Neil

AU - Koivula, Robert

AU - Elders, Petra J. M.

AU - Rauh, Simone P.

AU - Jones, Angus G.

AU - Holl, Reinhard W.

AU - Stingl, Julia C.

AU - Franks, Paul W.

AU - McCarthy, Mark I.

AU - t Hart, Leen M.

AU - Pearson, Ewan R.

AU - IMI DIRECT Consortium

PY - 2019/6/1

Y1 - 2019/6/1

N2 - 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.

AB - 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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UR - https://www.ncbi.nlm.nih.gov/pubmed/30885951

U2 - 10.2337/dc18-2182

DO - 10.2337/dc18-2182

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EP - 1033

JO - Diabetes Care

JF - Diabetes Care

SN - 0149-5992

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