Exendin-4 inhibits lipotoxicity-induced oxidative stress in β-cells by inhibiting the activation of TLR4/NF-κB signaling pathway

The present study aimed to investigate the relationship between the protective effects of exendin-4 (EX-4) on lipotoxicity-induced oxidative stress and meta-inflammation in beta-cells and the toll-like receptor 4 (TLR4)/NF-kappa B signaling pathway. Lipotoxicity, hydrogen peroxide (H2O2)-induced oxidative stress in beta cells, obese Sprague Dawley rats and TLR4 truncation rats were utilized in the present study. The expression levels were detected by western blotting; cell apoptosis was detected by TUNEL assay; and the intracellular reactive oxygen species (ROS) levels were analyzed using a ROS assay kit. The findings of the present study showed that EX-4 inhibited the expression of TLR4, NF-kappa B p65 subunit and p47(phox) in a concentration-dependent manner, and decreased the intracellular level of ROS. Additionally, silencing of TLR4 expression enhanced the protective effects of EX-4, while overexpression of TLR4 attenuated these protective influences. Simultaneously, it was demonstrated that TLR4 was involved in the process of EX-4 intervention to inhibit H2O2-induced oxidative stress in islet beta-cells. Moreover, it was found that EX-4 also inhibited TLR4- or NF-kappa B agonist-induced oxidative stress. These results were also confirmed in an animal model of obese rats, in which EX-4 was able to improve the function of beta-cells, attenuate oxidative stress, and inhibit the expression levels of TLR4 and NF-kappa B p65 subunit in the pancreas of the diet-induced obese rats. Furthermore, truncation of the TLR4 gene in SD rats delayed the aforementioned damage. In summary, EX-4 may inhibit lipotoxicity-induced oxidative stress in beta-cells by inhibiting the activation of the TLR4/NF-kappa B signaling pathway.