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%
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.
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.
BackgroundPeroxisome proliferator-activated receptor gamma 2 (PPAR-γ2) is a transcription factor with a key role in adipocyte differentiation, lipid storage and glucose homeostasis. The Ala allele of the common Pro12Ala polymorphism in the isoform PPAR-γ2 is at the center of many controversies because in some populations, it has been observed to be associated with T2DM or obesity but, not in others. The aim of this study was to investigate the association of Pro12Ala polymorphism in the PPAR-γ2 gene with susceptibility to obesity or T2DM in a Cameroonian population.MethodsThis case-control study included 62 obese, 60 T2DM patients and 120 controls (60 non obese and 60 patients without T2DM), all unrelated and of Cameroonian origin. PPAR-γ2 was examined by genotyping for Pro12Ala using the Restriction Fragment Length Polymorphism - Polymerase Chain Reaction (PCR - RFLP).ResultsA portion of the 270 base pair bands of the PPAR-γ2 gene was successfully amplified. The Ala12 variant was totally absent from the study population, all participants being homozygote Pro/Pro.ConclusionPPAR-γ2 Pro12Ala gene polymorphism may not be associated with obesity and T2DM. These results suggest that, PPAR-γ2 is unlikely a major gene for obesity or T2DM in the study population.
Identification of genetic/genomic factors contributing to dyslipidemia is of great interest to prevention and reduction of the onset and burden of cardiovascular diseases in Africa. This systematic review summarizes available data on genetic variants associated with dyslipidemia in populations within Africa. A PubMed and EMBASE database search was conducted to identify all studies published until June 2018 on genetic susceptibility to dyslipidemia in African-based populations, excluding familial hypercholesterolemia. All studies on genetic predispositions of dyslipidemia and respecting the preestablished inclusion criteria were included in this systematic review. Because of high heterogeneity, the data were summarized narratively. Twenty-two studies investigated mostly the targeted genetic variants. A total of 51 polymorphisms in 28 susceptibility genes to dyslipidemia have been associated with a particular trait in the African populations, and through variable effects. Most polymorphisms investigated in Northern Africa seemed to have consistent effects on increasing the level of low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglycerides in patients with diabetes, myocardial infarction, coronary artery disease, and metabolic syndrome. By contrast, only Ser447Ter and C49620T variants were associated with increased LDL-C in sub-Saharan Africa. Despite few studies available in this context in the literature, certain genetic variants were consistently associated with dyslipidemia especially in Northern Africa as highlighted in this analysis. Further data, particularly from genome-wide association studies, would help establish an African-specific reference for genetic susceptibility markers of dyslipidemia.
ObjectiveThis study aimed at investigating the association between the rs7903146 (C/T) polymorphism of the TCF7L2 gene with obesity in a Cameroonian population.MethodThis was a case-control pilot study including 61 obese and 61 non-obese Cameroonian adults. Anthropometric indices of obesity, blood pressure, fasting blood glucose, and blood lipids were measured. The rs7903146 (C/T) polymorphism of the TCF7L2 gene was genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and genotypes were correlated with clinical and biological parameters.ResultsThe T allele was predominant in the study population with a frequency of 93%. No statistically significant difference was however observed between the genotypic (p = 0.50) and allelic frequencies (p = 0.58) of obese and non-obese subjects. Comparison of clinical and biochemical parameters of C allele carriers (CX = CC + CT) with those of TT genotype showed that there was no significant difference between the lipid profile of these two groups.ConclusionThe rs7903146 (C/T) polymorphism of the TCF7L2 gene might not be associated with obesity in the Cameroonian population.
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