Metformin is the most commonly used treatment to increase insulin sensitivity in insulin-resistant (IR) conditions such as diabetes, prediabetes, polycystic ovary syndrome, and obesity. There is a well-documented correlation between glucose transporter 4 (GLUT4) expression and the level of IR. Therefore, the observed increase in peripheral glucose utilization after metformin treatment most likely comes from the induction of GLUT4 expression and its increased translocation to the plasma membrane. However, the mechanisms behind this effect and the critical metformin targets are still largely undefined. The present review explores the evidence for the crucial role of changes in the expression and activation of insulin signaling pathway mediators, AMPK, several GLUT4 translocation mediators, and the effect of posttranscriptional modifications based on previously published preclinical and clinical models of metformin’s mode of action in animal and human studies. Our aim is to provide a comprehensive review of the studies in this field in order to shed some light on the complex interactions between metformin action, GLUT4 expression, GLUT4 translocation, and the observed increase in peripheral insulin sensitivity.

Alcohol use disorder (AUD) is a highly prevalent, comorbid, and disabling disorder. The underlying mechanism of ethanol neurotoxicity and the involvement of oxidative stress is still not fully elucidated. However, ethanol metabolism has been associated with increased oxidative stress through alcohol dehydrogenase, the microsomal ethanol oxidation system, and catalase metabolic pathways. We searched the PubMed and genome-wide association studies (GWAS) catalog databases to review the literature systematically and summarized the findings focusing on AUD and alcohol abstinence in relation to oxidative stress. In addition, we reviewed the ClinicalTrials.gov resource of the US National Library of Medicine to identify all ongoing and completed clinical trials that include therapeutic interventions based on antioxidants. The retrieved clinical and preclinical studies show that oxidative stress impacts AUD through genetics, alcohol metabolism, inflammation, and neurodegeneration.

The degree of interpatient variability in the warfarin dose required to achieve the desired anticoagulant response can only partly be explained by polymorphisms in the CYP2C9 gene, suggesting that additional genetic factors such as polymorphisms in genes involved in blood coagulation may influence warfarin dose requirement. In total, 165 Caucasian outpatients on stable maintenance warfarin treatment previously genotyped for CYP2C9 were analysed for common polymorphisms in FVII, GGCX and VKORC1 genes. The -402G>A polymorphism and a variable number of repeats in intron 7 of FVII gene did not significantly influence warfarin dose.The mean warfarin doses increased with the number of (CAA) repeats in the GGCX gene, but the differences were significant only in the CYP2C9*1/*1 subgroup of patients (p=0.032). Common polymorphism (6484C>T) in intron 1 of the VKORC1 gene led to lower warfarin dose requirement; the means were 5.70 (95% C.I. 4.95 - 6.45), 3.49 (3.07 - 3.90) and 2.11 (1.80 - 2.42) mg/day for 6484 CC, CT and TT genotypes, respectively (pA polymorphism in 3’UTR of theVKORC1 gene led to higher warfarin dose requirement; the means were 3.09 (2.58 - 3.60), 4.26 (3.69 - 4.82) and 5.86 (4.53 - 7.19) mg/day for 9041 GG, GA and AA genotypes, respectively (p<0.001).With a regression model we explained 60.0% of variability in warfarin dose, which was due to gene polymorphisms (CYP2C9,VKORC1), age and body-surfacearea. When aiming for individualised warfarin therapy, at least VKORC1 polymorphisms should be included in predictive genotyping besides CYP2C9.