scholarly journals 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 ◽  
2019 ◽  
Vol 42 (6) ◽  
pp. 1027-1033 ◽  
Author(s):  
Adem Y. Dawed ◽  
Kaixin Zhou ◽  
Nienke van Leeuwen ◽  
Anubha Mahajan ◽  
Neil Robertson ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Plasma Membrane ◽  
Organic Cation ◽  
Organic Cation Transporter ◽  
Monoamine Transporter ◽  
Direct Study ◽  
Gastrointestinal Intolerance ◽  
Organic Cation Transporter 1

scholarly journals Variation in the plasma membrane monoamine transporter (PMAT, encoded in SLC29A4) and organic cation transporter 1 (OCT1, encoded in SLC22A1) and gastrointestinal intolerance to metformin in type 2 diabetes: an IMI DIRECT study

2018 ◽  
Author(s):  
Adem Y Dawed ◽  
Kaixin Zhou ◽  
Nienke van Leeuwen ◽  
Anubha Mahajan ◽  
Neil Robertson ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Plasma Membrane ◽  
Side Effects ◽  
Logistic Regression Model ◽  
Organic Cation ◽  
Organic Cation Transporter ◽  
Gastrointestinal Intolerance ◽  
Gastrointestinal Side Effects ◽  
Organic Cation Transporter 1

AbstractObjectives20-30% 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 MethodsThe 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.ResultsWomen (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).ConclusionsThese results suggest that intestinal metformin transporters and concomitant medications play an important role in gastrointestinal side effects of metformin.

scholarly journals Organic cation transporter 1 variants and gastrointestinal side effects of metformin in patients with Type 2 diabetes

2015 ◽  
Vol 33 (4) ◽  
pp. 511-514 ◽  
Author(s):  
T. Dujic ◽  
A. Causevic ◽  
T. Bego ◽  
M. Malenica ◽  
Z. Velija-Asimi ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Side Effects ◽  
Organic Cation ◽  
Organic Cation Transporter ◽  
Gastrointestinal Side Effects ◽  
Organic Cation Transporter 1

scholarly journals Genetic polymorphisms of organic cation transporter 1 (OCT1) and responses to metformin therapy in individuals with type 2 diabetes

Medicine ◽  
2018 ◽  
Vol 97 (27) ◽  
pp. e11349 ◽  
Author(s):  
Edith Pascale Mofo Mato ◽  
Magellan Guewo-Fokeng ◽  
M. Faadiel Essop ◽  
Peter Mark Oroma Owira
Keyword(s):  
Type 2 Diabetes ◽  
Genetic Polymorphisms ◽  
Organic Cation ◽  
Organic Cation Transporter ◽  
Metformin Therapy ◽  
Organic Cation Transporter 1

scholarly journals Association of Organic Cation Transporter 1 With Intolerance to Metformin in Type 2 Diabetes: A GoDARTS Study

Diabetes ◽  
2014 ◽  
Vol 64 (5) ◽  
pp. 1786-1793 ◽  
Author(s):  
Tanja Dujic ◽  
Kaixin Zhou ◽  
Louise A. Donnelly ◽  
Roger Tavendale ◽  
Colin N.A. Palmer ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Organic Cation ◽  
Organic Cation Transporter ◽  
Organic Cation Transporter 1

scholarly journals Role of Organic Cation Transporter 3 and Plasma Membrane Monoamine Transporter in the Rewarding Properties and Locomotor Sensitizing Effects of Amphetamine in Male andFemale Mice

2021 ◽  
Vol 22 (24) ◽  
pp. 13420
Author(s):  
Nikki J. Clauss ◽  
Wouter Koek ◽  
Lynette C. Daws
Keyword(s):  
Plasma Membrane ◽  
Knockout Mice ◽  
Organic Cation ◽  
Organic Cation Transporter ◽  
Monoamine Transporter ◽  
Stimulant Effect ◽  
Stimulant Drugs ◽  
Males And Females ◽  
Organic Cation Transporter 3

A lack of effective treatment and sex-based disparities in psychostimulant addiction and overdose warrant further investigation into mechanisms underlying the abuse-related effects of amphetamine-like stimulants. Uptake-2 transporters such as organic cation transporter 3 (OCT3) and plasma membrane monoamine transporter (PMAT), lesser studied potential targets for the actions of stimulant drugs, are known to play a role in monoaminergic neurotransmission. Our goal was to examine the roles of OCT3 and PMAT in mediating amphetamine (1 mg/kg)-induced conditioned place preference (CPP) and sensitization to its locomotor stimulant effects, in males and females, using pharmacological, decynium-22 (D22; 0.1 mg/kg, a blocker of OCT3 and PMAT) and genetic (constitutive OCT3 and PMAT knockout (−/−) mice) approaches. Our results show that OCT3 is necessary for the development of CPP to amphetamine in males, whereas in females, PMAT is necessary for the ability of D22 to prevent the development of CPP to amphetamine. Both OCT3 and PMAT appear to be important for development of sensitization to the locomotor stimulant effect of amphetamine in females, and PMAT in males. Taken together, these findings support an important, sex-dependent role of OCT3 and PMAT in the rewarding and locomotor stimulant effects of amphetamine.

scholarly journals Electrophysiological Characterization of the Polyspecific Organic Cation Transporter Plasma Membrane Monoamine Transporter

2012 ◽  
Vol 40 (6) ◽  
pp. 1138-1143 ◽  
Author(s):  
Shiro Itagaki ◽  
Vadivel Ganapathy ◽  
Horace T. B. Ho ◽  
Mingyan Zhou ◽  
Ellappan Babu ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Organic Cation ◽  
Organic Cation Transporter ◽  
Monoamine Transporter ◽  
Electrophysiological Characterization
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