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      Impact of ATM and SLC22A1 Polymorphisms on Therapeutic Response to Metformin in Iranian Diabetic Patients

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          Abstract

          Metabolic syndrome and its pathological sequel, type 2 diabetes are considered as important global health problems. Metformin is the most common drug prescribed for patients with this disorder. Consequently, understanding the genetic pathways involved in pharmacokinetics and pharmacodynamics of this drug can have a considerable effect on the personalized treatment of type 2 diabetes. In this study, we evaluated the association between rs11212617 polymorphism of ATM gene and rs628031 of SLC22A1 gene with response to treatment in newly diagnosed type 2 diabetes patients. We genotyped rs11212617 and rs628031 polymorphism by PCR based restriction fragment length polymorphism (RFLP) and assessed the role of this polymorphisms on response to treatment in 140 patients who have been recently diagnosed with type 2 diabetes and were under monotherapy with metformin for 6 months. Response to metformin was defined by HbA1c and fasting blood sugar (FBS) values. Based on such evaluations, patients were divided into two groups: responders (n= 63) and non-responders (n= 77). No significant association was found between these polymorphisms and response to treatment (OR= 0.86, [95% CI 0.52–1.41], P= 0.32) for rs11212617 and (OR= 0.45, [95% CI 0.64–1.76], P= 0.45) for rs 628031. The reported gene variants in ATM and SLC22A1 are not significantly associated with metformin treatment response in type 2 diabetic patients in an Iranian population.

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          Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes

          Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We carried out a GWA study on glycaemic response to metformin in 1024 Scottish patients with type 2 diabetes. Replication was in two cohorts consisting of 1783 Scottish patients and 1113 patients from the UK Prospective Diabetes Study. In a meta-analysis (n=3920) we observed an association (P=2.9 *10−9) for a SNP rs11212617 at a locus containing the ataxia telangiectasia mutated (ATM) gene with an odds ratio of 1.35 (95% CI 1.22 to 1.49) for treatment success. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMPK in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMPK, and variation in this gene alters glycaemic response to metformin.
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            The Effect of Oral Antidiabetic Agents on A1C Levels

            OBJECTIVE Previous reviews of the effect of oral antidiabetic (OAD) agents on A1C levels summarized studies with varying designs and methodological approaches. Using predetermined methodological criteria, we evaluated the effect of OAD agents on A1C levels. RESEARCH DESIGN AND METHODS The Excerpta Medica (EMBASE), the Medical Literature Analysis and Retrieval System Online (MEDLINE), and the Cochrane Central Register of Controlled Trials databases were searched from 1980 through May 2008. Reference lists from systematic reviews, meta-analyses, and clinical practice guidelines were also reviewed. Two evaluators independently selected and reviewed eligible studies. RESULTS A total of 61 trials reporting 103 comparisons met the selection criteria, which included 26,367 study participants, 15,760 randomized to an intervention drug(s), and 10,607 randomized to placebo. Most OAD agents lowered A1C levels by 0.5−1.25%, whereas thiazolidinediones and sulfonylureas lowered A1C levels by ∼1.0–1.25%. By meta-regression, a 1% higher baseline A1C level predicted a 0.5 (95% CI 0.1–0.9) greater reduction in A1C levels after 6 months of OAD agent therapy. No clear effect of diabetes duration on the change in A1C with therapy was noted. CONCLUSIONS The benefit of initiating an OAD agent is most apparent within the first 4 to 6 months, with A1C levels unlikely to fall more than 1.5% on average. Pretreated A1C levels have a modest effect on the fall of A1C levels in response to treatment.
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              Meta-analysis: metformin treatment in persons at risk for diabetes mellitus.

              We performed a meta-analysis of randomized controlled trials to assess the effect of metformin on metabolic parameters and the incidence of new-onset diabetes in persons at risk for diabetes. We performed comprehensive English- and non-English-language searches of EMBASE, MEDLINE, and CINAHL databases from 1966 to November of 2006 and scanned selected references. We included randomized trials of at least 8 weeks duration that compared metformin with placebo or no treatment in persons without diabetes and evaluated body mass index, fasting glucose, fasting insulin, calculated insulin resistance, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and the incidence of new-onset diabetes. Pooled results of 31 trials with 4570 participants followed for 8267 patient-years showed that metformin reduced body mass index (-5.3%, 95% confidence interval [CI], -6.7--4.0), fasting glucose (-4.5%, CI, -6.0--3.0), fasting insulin (-14.4%, CI, -19.9--8.9), calculated insulin resistance (-22.6%, CI, -27.3--18.0), triglycerides (-5.3%, CI, -10.5--0.03), and low-density lipoprotein cholesterol (-5.6%, CI, -8.3--3.0%), and increased high-density lipoprotein cholesterol (5.0%, CI, 1.6-8.3) compared with placebo or no treatment. The incidence of new-onset diabetes was reduced by 40% (odds ratio 0.6; CI, 0.5-0.8), with an absolute risk reduction of 6% (CI, 4-8) during a mean trial duration of 1.8 years. Metformin treatment in persons at risk for diabetes improves weight, lipid profiles, and insulin resistance, and reduces new-onset diabetes by 40%. The long-term effect on morbidity and mortality should be assessed in future trials.
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                Author and article information

                Journal
                Int J Mol Cell Med
                Int J Mol Cell Med
                IJMCM
                International Journal of Molecular and Cellular Medicine
                Babol University of Medical Sciences (Babol, Iran )
                2251-9637
                2251-9645
                Winter 2016
                : 5
                : 1
                : 1-7
                Affiliations
                [1 ] Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
                [2 ] Immunogenetic Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
                [3 ] Department of Clinical Biochemistry and Genetics, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
                [4 ] Diabetes Research Center, Imam Teaching Hospital, Mazandaran University of Medical Sciences, Sari, Iran .
                Author notes
                [* ]Corresponding author: Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. E-mail: davood_omrani@sbmu.ac.ir
                Article
                ijmcm-5-001
                4916778
                27386433
                562bc707-ca1b-4619-b1ec-ccd827cf4f8b

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License, ( http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 15 November 2015
                : 7 December 2015
                : 5 March 2016
                Categories
                Original Article

                metformin,type 2 diabetes,pharmacogenetic
                metformin, type 2 diabetes, pharmacogenetic

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