TABLE 1.
In Vitro studies evaluating the antioxidant action of metformin.
| Model | Dose | Parameters | Results | References | Limitations |
|---|---|---|---|---|---|
| human umbilical vein endothelial cells | 2 mmol/L | increased production of nitric oxide | activated guanosine 5′-triphosphate cyclohydrolase 1 | An et al. (2016) | Alteration in eNOS Activity (alteration in the activity of eNOS in response to FG) |
| decreased reactive oxygen species production | recoupling of endothelial nitric oxide synthase | Despite the upregulation of phosphorylated eNOS, there are simultaneous changes in the generation of ROS and the production of nitric oxide (NO) under the influence of FG, eNOS becomes uncoupled. Instead of performing its normal role as an enzyme producing NO, eNOS is converted into a molecule that generates superoxide, which is a type of ROS | |||
| inhibited nicotinamide adenine dinucleotide phosphate via an AMP-activated protein kinase | |||||
| human aortic endothelial cells | 250 µM | reducing reactive oxygen species production, increase in the concentration of the antioxidant thioredoxin | upregulate the expression of the forkhead transcription factor 3 through the AMPK pathway | Hou et al. (2010) | various types of FOXOs may have different, and even |
| opposite, effects on ROS level | |||||
| human endothelial cells | 1 mM | reducing reactive oxygen species production | downregulation of NADPH Oxidase 4 activity | Cheng and Lanza-Jacoby (2015) | NA |
| aortic endothelial cells | 1–5 μmol/L | reducing reactive oxygen species production | regulation of NADPH oxidase activity | Ouslimani et al. (2005) | Lack in chelation of intracellular metal ions by Metformin assessment; a contact of cells with culture medium free of metformin for 1 h or 2 h before the experiments |
| peripheral blood mononuclear human cells | 2 µM | Increased of superoxide dismutase, catalase, and glutathione peroxidase activity, reducing reactive oxygen species production | decrease in the expression of NADPH oxidase upregulating key antioxidative enzymes | Bułdak et al. (2016) | Metformin exerts a mild effect on catalase expression, statistically small sample size, a predominant effect of metformin on the catalytic activity of the catalase enzyme |
| rat adipocytes | 4 mM | increased UCP2 levels | UCP adipocytes pathway | Anedda et al. (2008) | The upregulation of UCP2 induced by leptin, when lipolysis and β-oxidation are also promoted, could indicate that there are all involved in energy dissipation (misleading results); polymorphisms in the human UCP2 |
| increase of ROS | |||||
| decrease in aconitase activity | |||||
| H4II rat hepatocellular carcinoma cells | 5 mM | Increase in ROS | Apoptosis induction in cancer cells | Park (2019) | unclear by which pathway metformin |
| Decrease in NAC | induces ROS generation |
FG, fluctuating glucose; NA, not applicable; NAC, N-acetylcysteine; NADPH, nicotinamide adenine dinucleotide phosphate; UCP2, uncoupling proteins; ROS, reactive oxygen species.