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Reduced-function SLC22A1 polymorphisms encoding organic cation transporter 1 and glycemic response to metformin: a GoDARTS study.

Zhou K, Donnelly LA, Kimber CH, Donnan PT, Doney AS, Leese G, Hattersley AT, McCarthy MI, Morris AD, Palmer CN, Pearson ER - Diabetes (2009)

Bottom Line: 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.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).The SLC22A1 loss-of-function variants, R61C and 420del, do not attenuate the A1C reduction achieved by metformin in patients with type 2 diabetes.

View Article: PubMed Central - PubMed

Affiliation: Dundee Diabetes Genetics Group, Biomedical Research Institute, University of Dundee, Dundee, 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.

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Related in: MedlinePlus

Flowchart of patients' ascertainment. In the mini genotype frequency tables, W/W denotes the wild-type homozygote, M/M denotes the rare homozygote of CC and Del/Del for R61C and 420del, respectively, and W/M denotes heterozygote. DOB, date of birth.
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Figure 1: Flowchart of patients' ascertainment. In the mini genotype frequency tables, W/W denotes the wild-type homozygote, M/M denotes the rare homozygote of CC and Del/Del for R61C and 420del, respectively, and W/M denotes heterozygote. DOB, date of birth.

Mentions: Patients were selected from an ongoing study of the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS). (Additional information is available in an online appendix [http://diabetes.diabetesjournals.org/cgi/content/full/db08-0896/DC1].) All incident users of metformin (n = 3,450) were included to identify patients informative for the current study following the ascertainment process outlined in Fig. 1. Two study groups were defined, each of which required complete data with respect to sex, age, metformin dose, adherence, and A1C response. The subjects in group 1 received no diabetes-related drug treatment for at least 6 months before their index metformin prescription and were thus considered treatment naive. The subjects in group 2 were stably treated with oral hypoglycemic agents for at least 6 months before starting metformin and until at least the A1C on metformin therapy was measured. Both groups required at least 6 months of metformin use. The study was approved by the Tayside Medical Ethics Committee, and informed consent was obtained from all subjects.


Reduced-function SLC22A1 polymorphisms encoding organic cation transporter 1 and glycemic response to metformin: a GoDARTS study.

Zhou K, Donnelly LA, Kimber CH, Donnan PT, Doney AS, Leese G, Hattersley AT, McCarthy MI, Morris AD, Palmer CN, Pearson ER - Diabetes (2009)

Flowchart of patients' ascertainment. In the mini genotype frequency tables, W/W denotes the wild-type homozygote, M/M denotes the rare homozygote of CC and Del/Del for R61C and 420del, respectively, and W/M denotes heterozygote. DOB, date of birth.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2682689&req=5

Figure 1: Flowchart of patients' ascertainment. In the mini genotype frequency tables, W/W denotes the wild-type homozygote, M/M denotes the rare homozygote of CC and Del/Del for R61C and 420del, respectively, and W/M denotes heterozygote. DOB, date of birth.
Mentions: Patients were selected from an ongoing study of the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS). (Additional information is available in an online appendix [http://diabetes.diabetesjournals.org/cgi/content/full/db08-0896/DC1].) All incident users of metformin (n = 3,450) were included to identify patients informative for the current study following the ascertainment process outlined in Fig. 1. Two study groups were defined, each of which required complete data with respect to sex, age, metformin dose, adherence, and A1C response. The subjects in group 1 received no diabetes-related drug treatment for at least 6 months before their index metformin prescription and were thus considered treatment naive. The subjects in group 2 were stably treated with oral hypoglycemic agents for at least 6 months before starting metformin and until at least the A1C on metformin therapy was measured. Both groups required at least 6 months of metformin use. The study was approved by the Tayside Medical Ethics Committee, and informed consent was obtained from all subjects.

Bottom Line: 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.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).The SLC22A1 loss-of-function variants, R61C and 420del, do not attenuate the A1C reduction achieved by metformin in patients with type 2 diabetes.

View Article: PubMed Central - PubMed

Affiliation: Dundee Diabetes Genetics Group, Biomedical Research Institute, University of Dundee, Dundee, 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.

Show MeSH
Related in: MedlinePlus