Abstract:  Objective To investigate the possible mechanisms of glucagon- like peptide 1 receptor agonists (GLP-1Ra) protection against hyperglycemic induced beta cell apoptosis through depression of NOX2-dependent ROS production. Methods The rat model of type 2 diabetes (T2DM) was established by injecting small doses of streptozotocin (STZ) followed by 8-week high fat diet. The experimental animals were divided into three groups: normal control (N) group, diabetes (T2DM) group and GLP-1Ra group [treated with liraglutide 200 μg/ （kg·d）for 12 weeks]. The blood glucose levels were compared before and after modeling, before treatment and 12-week after treatment with GLP-1Ra. The level of glycosylated hemoglobin (HbA1c) was detected by high-pressure liquid chromatography. Automatic biochemical analyzer was used to detect levels of aspertate aminotransferase (AST), creatinine (CR) and urea nitrogen (BUN). The apoptotic rates of islets were determined by TUNEL method and cleaved caspase 3 was detected by immunohistochemistry. DCFH-DA fluorescent probe was used to detect reactive oxygen species (ROS) levels of islets. Levels of NADPH oxidase (NOX) catalytic subunit (NOX2) in islets were measured by immunohistochemistry. Results At the end of the study, glycemic control (average blood glucose/week and HbA1c) and lipid situation were improved significantly in the GLP-1Ra group than those of N group (P＜0.05). TUNEL staining and displayed that β cell apoptotic and cleaved caspase 3 level were significantly decreased in GLP-1Ra group compared to those of T2DM group (P＜0.05). ROS levels were significantly decreased in GLP-1Ra group than those of T2DM group before treatment with Apocynin, but no significant difference between GLP1-Ra group and N group (P＞0.05). After application Apocynin for inhibition, there were no significant differences between three groups (P＞0.05). The level of NOX2 was significantly lower in GLP-1Ra group compared to that of T2DM group (P＜0.05). Conclusion GLP-1Ra can inhibit apoptosis of β cells in diabetes rat, and the depression of NOX2-dependent ROS may be one of the important underlying mechanisms.

Key words: diabetes , type 2, disease models, animal, Glucagon-like peptide-1, NOX2, oxidative stress , apoptosis, liraglutide, ROS