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Reduced-Function SLC22A1 Polymorphisms Encoding Organic Cation Transporter 1 and Glycemic Response to Metformin: A GoDARTS Study
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...
Autores principales: | , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682689/ https://www.ncbi.nlm.nih.gov/pubmed/19336679 http://dx.doi.org/10.2337/db08-0896 |
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author | Zhou, Kaixin Donnelly, Louise A. Kimber, Charlotte H. Donnan, Peter T. Doney, Alex S.F. Leese, Graham Hattersley, Andrew T. McCarthy, Mark I. Morris, Andrew D. Palmer, Colin N.A. Pearson, Ewan R. |
author_facet | Zhou, Kaixin Donnelly, Louise A. Kimber, Charlotte H. Donnan, Peter T. Doney, Alex S.F. Leese, Graham Hattersley, Andrew T. McCarthy, Mark I. Morris, Andrew D. Palmer, Colin N.A. Pearson, Ewan R. |
author_sort | Zhou, Kaixin |
collection | PubMed |
description | 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. |
format | Text |
id | pubmed-2682689 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-26826892010-06-01 Reduced-Function SLC22A1 Polymorphisms Encoding Organic Cation Transporter 1 and Glycemic Response to Metformin: A GoDARTS Study Zhou, Kaixin Donnelly, Louise A. Kimber, Charlotte H. Donnan, Peter T. Doney, Alex S.F. Leese, Graham Hattersley, Andrew T. McCarthy, Mark I. Morris, Andrew D. Palmer, Colin N.A. Pearson, Ewan R. Diabetes Genetics 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. American Diabetes Association 2009-06 2009-03-31 /pmc/articles/PMC2682689/ /pubmed/19336679 http://dx.doi.org/10.2337/db08-0896 Text en © 2009 by the American Diabetes Association. |
spellingShingle | Genetics Zhou, Kaixin Donnelly, Louise A. Kimber, Charlotte H. Donnan, Peter T. Doney, Alex S.F. Leese, Graham Hattersley, Andrew T. McCarthy, Mark I. Morris, Andrew D. Palmer, Colin N.A. Pearson, Ewan R. Reduced-Function SLC22A1 Polymorphisms Encoding Organic Cation Transporter 1 and Glycemic Response to Metformin: A GoDARTS Study |
title | Reduced-Function SLC22A1 Polymorphisms Encoding Organic Cation Transporter 1 and Glycemic Response to Metformin: A GoDARTS Study |
title_full | Reduced-Function SLC22A1 Polymorphisms Encoding Organic Cation Transporter 1 and Glycemic Response to Metformin: A GoDARTS Study |
title_fullStr | Reduced-Function SLC22A1 Polymorphisms Encoding Organic Cation Transporter 1 and Glycemic Response to Metformin: A GoDARTS Study |
title_full_unstemmed | Reduced-Function SLC22A1 Polymorphisms Encoding Organic Cation Transporter 1 and Glycemic Response to Metformin: A GoDARTS Study |
title_short | Reduced-Function SLC22A1 Polymorphisms Encoding Organic Cation Transporter 1 and Glycemic Response to Metformin: A GoDARTS Study |
title_sort | reduced-function slc22a1 polymorphisms encoding organic cation transporter 1 and glycemic response to metformin: a godarts study |
topic | Genetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682689/ https://www.ncbi.nlm.nih.gov/pubmed/19336679 http://dx.doi.org/10.2337/db08-0896 |
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