Reduced-Function SLC22A1 Polymorphisms Encoding Organic Cation Transporter 1 and Glycemic Response to Metformin: A GoDARTS Study
Kaixin Zhou 1 ,
Louise A. Donnelly 1 ,
Charlotte H. Kimber 1 ,
Peter T. Donnan 2 ,
Alex S.F. Doney 3 ,
Graham Leese 3 , 4 ,
Andrew T. Hattersley 5 ,
Mark I. McCarthy 6 , 7 ,
Andrew D. Morris 1 , 4 ,
Colin N.A. Palmer 1 , 4 and
Ewan R. Pearson 1 , 4
1 Dundee Diabetes Genetics Group, Biomedical Research Institute, University of Dundee, Dundee, U.K.;
2 Health Informatics Centre, University of Dundee, Dundee, U.K.;
3 Ninewells Hospital and Medical School, Dundee, U.K.;
4 Diabetes Research Centre, University of Dundee, Dundee, U.K.;
5 Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, U.K.;
6 Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, U.K.;
7 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.
Corresponding author: Ewan R. Pearson, e.pearson{at}chs.dundee.ac.uk .
Abstract
OBJECTIVE Metformin is actively transported into the liver by the organic cation transporter (OCT)1 (encoded by SLC22A1 ). In 12 normoglycemic individuals, reduced-function variants in SLC22A1 were shown to decrease the ability of metformin to reduce glucose excursion in response to oral glucose. We assessed the
effect of two common loss-of-function polymorphisms in SLC22A1 on metformin response in a large cohort of patients with type 2 diabetes.
RESEARCH DESIGN AND METHODS The Diabetes Audit and Research in Tayside Scotland (DARTS) database includes prescribing and biochemistry information and
clinical phenotypes of all patients with diabetes within Tayside, Scotland, from 1992 onwards. R61C and 420del variants of
SLC22A1 were genotyped in 3,450 patients with type 2 diabetes who were incident users of metformin. We assessed metformin response
by modeling the maximum A1C reduction in 18 months after starting metformin and investigated whether a treatment target of
A1C <7% was achieved. Sustained metformin effect on A1C between 6 and 42 months was also assessed, as was the time to metformin
monotherapy failure. Covariates were SLC22A1 genotype, BMI, average drug dose, adherence, and creatinine clearance.
RESULTS A total of 1,531 patients were identified with a definable metformin response. R61C and 420del variants did not affect the
initial A1C reduction ( P = 0.47 and P = 0.92, respectively), the chance of achieving a treatment target ( P = 0.83 and P = 0.36), the average A1C on monotherapy up to 42 months ( P = 0.44 and P = 0.75), or the hazard of monotherapy failure ( P = 0.85 and P = 0.56).
CONCLUSIONS The SLC22A1 loss-of-function variants, R61C and 420del, do not attenuate the A1C reduction achieved by metformin in patients with type
2 diabetes.
Footnotes
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Received July 4, 2008.
Accepted March 18, 2009.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
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© 2009 by the American Diabetes Association....

Reduced-Function SLC22A1 Polymorphisms Encoding Organic Cation Transporter 1 and Glycemic Response to Metformin: A GoDARTS Study

10.2337/db08-0896