Effects of Metformin on oxidative stress, adenine nucleotides balance and glucose-induced insulin release impaired by chronic FFA exposure in rat pancreatic islets

Background: In rat pancreatic islets, chronic exposure to high free fatty acid (FFA) levels impairs insulin secretion and beta cell mass. The mechanisms underlying this defect are not completely understood. Since islets have intrinsically low antioxidant enzyme defense, oxidative stress might be responsible for beta cell damage. Aim: In this study, we investigated if FFA could induce oxidative stress in rat pancreatic islets and if metformin might reverse adverse effects. Material and Methods: We cultured rat pancreatic islets in the presence or absence of FFA (oleate/palmitate 2:1, 2 mM) for 72 h. In some experiments, we used metformin (2.5 μg/mL) during the last 24 h. Results: In our model, glucose-stimulated insulin release was markedly reduced (p<0.005) after chronic FFA exposure, and the ATP/ADP ratio was altered (p<0.05). We observed a significant increase of ROS (Reactive Oxygen Species) (p<0.001), MDA (malondialdehyde) a lipid peroxidation product (p<0.01) and NO (nitric oxide) levels in the culture media (p<0.001). iNOS (inducible nitric oxide synthase) and HSP-70 (Heat Shock Protein-70) protein expression were also increased (p<0.001 and p<0.01, respectively). When metformin was present during the last 24 h of culture, insulin secretion was restored, and the ATP/ADP ratio was normalized. ROS production, NO production, lipid peroxidation, iNOS and HSP-70 protein expression levels were decreased. Conclusions: These data indicate that, in rat pancreatic islets, chronic exposure to high FFA induces oxidative stress and that metformin, by reducing this effect, may have a direct beneficial effect on insulin secretion impaired by lipotoxicity.