The variant organic cation transporter 2 (OCT2)–T201M contribute to changes in insulin resistance in patients with type 2 diabetes treated with metformin

Kashi, Zahra; Masoumi, Parisa; Mahrooz, Abdolkarim; Hashemi‐Soteh, Mohammad Bagher; Aydınlı, Bahar; Alizadeh, Ahad

doi:10.1016/j.diabres.2015.01.024

Cited by 22 publications

(17 citation statements)

References 24 publications

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“…The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommend lifestyle modifications and initiation of metformin therapy in newly diagnosed patients with T2DM [ 4 ]. Metformin is the most frequently used antidiabetic drug for the management of T2DM [ 4 , 5 ]. It inhibits hepatic glucose production, increases glucose uptake, suppresses the gastric absorption of glucose, and serves as an insulin sensitizer [ 4 , 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

The Role of Metformin Response in Lipid Metabolism in Patients with Recent-Onset Type 2 Diabetes: HbA1c Level as a Criterion for Designating Patients as Responders or Nonresponders to Metformin

et al. 2016

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BackgroundIn this study, we investigated whether response to metformin, the most frequently drug for diabetes treatment, influences the therapeutic effects of antilipidemic medication in newly diagnosed patients with type 2 diabetes mellitus (T2DM).MethodsA total of 150 patients with T2DM were classified into two groups following 3 months of metformin therapy (1000 mg twice daily): responders (patients showing ≥1% reduction in HbA1c from baseline) and nonresponders (patients showing <1% reduction in HbA1c from baseline). The patients received atorvastatin 20 mg, gemfibrozil 300 mg, or atorvastatin 20 mg and gemfibrozil 300 mg daily.Principal FindingsHbA1c and fasting glucose levels were significantly different between baseline and 3 months among responders receiving atorvastatin; however, these differences were not statistically significant in nonresponders. Atherogenic ratios of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol (LDL-C/HDL-C; p = 0.002), total cholesterol to HDL-C (TC/HDL-C; p<0.001) and AIP (the atherogenic index of plasma; p = 0.004) decreased significantly in responders receiving atorvastatin than in nonresponders. Moreover, responders receiving atorvastatin showed a significant increase in HDL-C levels but nonresponders receiving atorvastatin did not (p = 0.007). The multivariate model identified a significant association between metformin response (as the independent variable) and TG, TC, HDL-C and LDL-C (dependent variables; Wilk's λ = 0.927, p = 0.036).ConclusionsMetformin response affects therapeutic outcomes of atorvastatin on atherogenic lipid markers in patients newly diagnosed with T2DM. Metformin has a greater impact on BMI in responders of metformin compared to nonresponders. Adoption of better therapeutic strategies for reducing atherogenic lipid markers may be necessary for metformin nonresponders.

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Section: Introductionmentioning

confidence: 99%

The Role of Metformin Response in Lipid Metabolism in Patients with Recent-Onset Type 2 Diabetes: HbA1c Level as a Criterion for Designating Patients as Responders or Nonresponders to Metformin

et al. 2016

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“…[78] In general, the mechanisms of metformin action include reduction of hepatic glucose production, increased glucose uptake in skeletal tissue, suppression of the intestinal absorption of glucose, and improvement of insulin sensitivity. [910] Metformin reduces triglyceride (TG) levels, free fatty acids, and low-density lipoprotein (LDL) in plasma and increases high-density lipoprotein (HDL).…”

Section: Introductionmentioning

confidence: 99%

Allele frequency and genotype distribution of a common variant in the 3´-untranslated region of the SLC22A3 gene in patients with type 2 diabetes: Association with response to metformin

et al. 2016

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Background:Organic cation transporter 3 (OCT3) is an excellent transporter for metformin, which is used as first-line therapy for type 2 diabetes (T2D). OCT3 genetic variants may influence the clinical response to metformin. This study aimed to determine the genotype and allele frequency of OCT3-564G>A (rs3088442) variant and its role in the glycemic response to metformin in patients with newly diagnosed T2D.Materials and Methods:Based on the response to metformin, 150 patients were classified into two groups: Sixty-nine responders (decrease in glycated hemoglobin [HbA1c] values by more than 1% from the baseline) and 81 nonresponders (decrease in HbA1c values <1% from the baseline). HbA1c levels were determined by chromatography. The variant OCT3-564G>A was genotyped using polymerase chain reaction - based restriction fragment length polymorphism.Results:The genotypes frequencies were 51.3% GG, 36% AG, and 12.7% AA. Allele frequency of major allele (G) and minor allele (A) in OCT3-564G>A variant was found to be 0.69 and 0.31, respectively. Fasting glucose, HbA1c, body mass index, and lipid profile in both GG genotypes and GA + AA group decreased significantly after 3 months of metformin therapy compared with baseline (P < 0.05). In both responders and nonresponders, HbA1c and fasting glucose levels were lower in patients with the GA + AA genotype than in those with the GG genotype; however, the differences were not statistically significant (P > 0.05).Conclusion:The A allele frequency (which may be a protective allele against coronary heart disease) in the Iranian diabetic patients was lower than Iranian, Caucasian and Japanese healthy populations. Metformin is useful in improving the lipid profile, in addition to its impacts in glycemic control, and these effects are regardless of OCT3-564G>A variant.

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“…Three nonsynonymous variants, rs145450955 (Thr201Met), rs316019 (Ala270Ser), and rs201919874 (Thr199Ile), were repeatedly shown to influence MET uptake, tubular excretion and clearance, consistent with an increase in circulating MET concentrations, both in vitro and in vivo . Among Iranian T2DM patients treated with MET, carriers of 201Met exhibited higher‐HbA1c concentrations, fasting glucose levels, and homeostasis model assessment of insulin resistance (HOMA‐IR), and a possible sex specificity, which had never been reported previously . In a small number of Chinese T2DM patients of novel diagnosis, a significantly stronger decrease in HbA1c was observed in heterozygous compared with wild‐type 270Ala homozygous after 1 year of treatment with MET, upon adjustment for baseline HbA1c, exercise, and diet .…”

Section: Summary Of the Literaturementioning

confidence: 91%

Pharmacogenetics of type 2 diabetes mellitus, the route toward tailored medicine

Mannino

Andreozzi

Sesti

2019

Diabetes Metabolism Res

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Summary Type 2 diabetes mellitus (T2DM) is a chronic disease that has reached the levels of a global epidemic. In order to achieve optimal glucose control, it is often necessary to rely on combination therapy of multiple drugs or insulin because uncontrolled glucose levels result in T2DM progression and enhanced risk of complications and mortality. Several antihyperglycemic agents have been developed over time, and T2DM pharmacotherapy should be prescribed based on suitability for the individual patient's characteristics. Pharmacogenetics is the branch of genetics that investigates how our genome influences individual responses to drugs, therapeutic outcomes, and incidence of adverse effects. In this review, we evaluated the pharmacogenetic evidences currently available in the literature, and we identified the top informative genetic variants associated with response to the most common anti‐diabetic drugs: metformin, DPP‐4 inhibitors/GLP1R agonists, thiazolidinediones, and sulfonylureas/meglitinides. Overall, we found 40 polymorphisms for each drug class in a total of 71 loci, and we examined the possibility of encouraging genetic screening of these variants/loci in order to critically implement decision‐making about the therapeutic approach through precision medicine strategies. It is possible then to anticipate that when the clinical practice will take advantage of the genetic information of the diabetic patients, this will provide a useful resource for the prevention of T2DM progression, enabling the identification of the precise drug that is most likely to be effective and safe for each patient and the reduction of the economic impact on a global scale.

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The variant organic cation transporter 2 (OCT2)–T201M contribute to changes in insulin resistance in patients with type 2 diabetes treated with metformin

Cited by 22 publications

References 24 publications

The Role of Metformin Response in Lipid Metabolism in Patients with Recent-Onset Type 2 Diabetes: HbA1c Level as a Criterion for Designating Patients as Responders or Nonresponders to Metformin

The Role of Metformin Response in Lipid Metabolism in Patients with Recent-Onset Type 2 Diabetes: HbA1c Level as a Criterion for Designating Patients as Responders or Nonresponders to Metformin

Allele frequency and genotype distribution of a common variant in the 3´-untranslated region of the SLC22A3 gene in patients with type 2 diabetes: Association with response to metformin

Pharmacogenetics of type 2 diabetes mellitus, the route toward tailored medicine

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