Background:Metformin is one of the most commonly used drugs for the treatment of type 2 diabetes mellitus (T2DM). Despite its widespread use, there are considerable interindividual variations in metformin response, with about 35% of patients failing to achieve initial glycemic control. These variabilities that reflect phenotypic differences in drug disposition and action may indeed be due to polymorphisms in genes that regulate pharmacokinetics and pharmacodynamics of metformin. Moreover, interethnic differences in drug responses in some cases correspond to substantial differences in the frequencies of the associated pharmacogenomics risk allele.Aim:This study aims to highlight and summarize the overall effects of organic cation transporter 1(OCT1) polymorphisms on therapeutic responses to metformin and to evaluate the potential role of such polymorphisms in interethnic differences in metformin therapy.Methods:We conducted a systematic review according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. We searched for PubMed/MEDLINE, Embase, and CINAHL, relevant studies reporting the effects of OCT1 polymorphisms on metformin therapy in T2DM individuals. Data were extracted on study design, population characteristics, relevant polymorphisms, measure of genetic association, and outcomes. The presence of gastrointestinal side effects, glycated hemoglobin A1 (HbA1c) levels, fasting plasma glucose (FPG), and postprandial plasma glucose (PPG) concentrations after treatment with metformin were chosen as measures of the metformin responses. This systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO).Results:According to the data extracted, a total of 34 OCT1 polymorphisms were identified in 10 ethnic groups. Significant differences in the frequencies of common alleles were observed among these groups. Met408Val (rs628031) variant was the most extensively explored with metformin responses. Although some genotypes and alleles have been associated with deleterious effects on metformin response, others indeed, exhibited positive effects.Conclusion:Genetic effects of OCT1 polymorphisms on metformin responses were population specific. Further investigations in other populations are required to set ethnicity-specific reference for metformin responses and to obtain a solid basis to design personalized therapeutic approaches for T2DM treatment.

Objectives Antioxidant and anti‐inflammatory properties of naringenin could confer hepatoprotective effects. Methods Chang cells in culture media were maintained at 37°C and treated with increased concentrations of glucose (5.5–50 mm) and/or naringenin (25–100 µm), respectively, for 24 h. The cells were harvested and carbonyl proteins, antioxidant enzymes and proteins measured in cell lysates. Sprague Dawley rats were divided into 5 groups (n = 7) and orally treated daily for 56 days with 3.0 ml/kg per body weight (BW) distilled water (group 1), 60 mg/kg BW of naringenin (groups 2 and 4), respectively. Groups 3, 4 and 5 were given single 60 mg/kg per BW intraperitoneal injections of streptozotocin or insulin (2.0 IU/kg BW bid), (group 5 only). Key findings Cell viability was significantly decreased in response to increased hyperglycaemia but naringenin dose‐dependently, significantly reversed this compared to controls, respectively. However, antioxidant enzyme activities were reduced due to increased and reduced oxidative stress, respectively. Naringenin further significantly reduced hepatic oxidative stress and nuclear factor erythroid 2‐related factor 2 (Nrf2) protein expression and liver : body weight ratios in diabetic compared to controls rats. Conclusions Naringenin confers hepatoprotective antioxidant effects by initially preventing upregulation of Nrf2 protein expression and its downstream antioxidant enzymes.

Background and aims: Coronary artery disease (CAD) is a complex disease with a strong genetic basis. While previous studies have combined common single-nucleotide polymorphisms (SNPs) into a polygenic risk score (PRS) to predict CAD risk, this association is poorly characterised. We performed a meta-analysis to estimate the effect of PRS on the risk of CAD. Methods: Online databases were searched for studies reporting PRS and CAD. PRS computation was based on logodds (PRS LN ), pruning or clumping and thresholding (PRS P/C + T ), Lassosum regression (PRS Lassosum ), LDpred (PRS LDpred ), or metaGRS (PRS metaGRS ). The reported odds ratio (OR), hazard ratio (HR), C-indexes and their corresponding 95% confidence interval (95% CI) were pooled in a random-effects meta-analysis. Results: Forty-nine studies were included (979,286 individuals). There was a significant association between 1standard deviation [SD] increment in PRS and adjusted risks of both incident and prevalent CAD (OR [95%

Our studies show that the wild-type and the mutant constructs are regulated in a similar pattern under all conditions, strongly indicating that the -132 G/A mutation increases basal but not inducible transcription. These results may be explained by new binding to the mutant region through CREB and other transcription factors not yet identified.

BackgroundMetformin is one of the most commonly used drugs for type 2 diabetes mellitus (T2DM). Despite its efficacy and safety, metformin is frequently associated with highly variable glycemic responses, which is hypothesized to be the result of genetic variations in its transport by organic cation transporters (OCTs). This systematic review aims to highlight and summarize the overall effects of OCT1 polymorphisms on therapeutic responses to metformin and to evaluate their potential role in terms of interethnic differences with metformin responses.Methods/designWe will systematically review observational studies reporting on the genetic association between OCT1 polymorphisms and metformin responses in T2DM patients. A comprehensive search strategy formulated with the help of a librarian will be used to search MEDLINE via PubMed, Embase, and CINAHL for relevant studies published between January 1990 and July 2017. Two review authors will independently screen titles and abstracts in duplicate, extract data, and assess the risk of bias with discrepancies resolved by discussion or arbitration of a third review author. Mined data will be grouped according to OCT1 polymorphisms, and their effects on therapeutic responses to metformin will be narratively synthesized. If sufficient numbers of homogeneous studies are scored, meta-analyses will be performed to obtain pooled effect estimates. Funnel plots analysis and Egger’s test will be used to assess publication bias. This study will be reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines.DiscussionThis review will summarize the genetic effects of OCT1 polymorphisms associated with variabilities in glycemic responses to metformin. The findings of this study could help to develop genetic tests that could predict a person’s response to metformin treatment and create personalized drugs with greater efficacy and safety.Systematic review registrationRegistration number: PROSPERO, CRD42017079978Electronic supplementary materialThe online version of this article (10.1186/s13643-018-0773-y) contains supplementary material, which is available to authorized users.