Liraglutide ameliorates palmitate-induced oxidative injury in islet microvascular endothelial cells through GLP-1 receptor/PKA and GTPCH1/eNOS signaling pathways.

In type 2 diabetes, lipotoxicity damages islet microvascular endothelial cells (IMECs), leading to pancreatic islet β cell dysfunction directly or indirectly. Glucagon-like peptide-1 (GLP-1) and its analogs have beneficial roles in endothelial cells. However, the protective effects of GLP-1 agents on IMECs and their potential mechanism remained obscure. In this study, exposure of MS-1 (a cell line derived from mouse IMECs) to different concentrations of palmitic acid (PA) was used to establish an injury model. The cells exposed to PA (0.25 mmol/L) were treated with a GLP-1 analog liraglutide (3, 10, 30, and 100 nmol/L). Reactive oxygen species (ROS) generation, apoptosis-related protein level, and endothelin-1 production were detected. The protein levels of signaling molecules were analyzed and specific inhibitors or blockers were used to identify involvement of signaling pathways in the effects of liraglutide. Results showed that PA significantly increased ROS generation and the levels of pro-apoptotic protein Bax, and decreased the levels of anti-apoptotic protein Bcl-2 and the mRNA expression and secretion of endothelin-1. Meanwhile, PA downregulated the protein levels of GLP-1 receptor (GLP-1R), phosphorylated protein kinase A (PKA), guanosine 5'-triphosphate cyclohydrolase 1 (GTPCH1), and endothelial nitric oxide synthase (eNOS). Furthermore, liraglutide ameliorated all these effects of PA in a dose-dependent manner. Importantly, GLP-1R antagonist exendin (9-39), PKA inhibitor H89, GTPCH1 inhibitor 2,4-diamino-6-hydroxypyrimidine, or NOS inhibitor N-nitro-l-arginine-methyl ester abolished the liraglutide-mediated amelioration in PA-impaired MS-1 cells. In conclusion, liraglutide ameliorates the PA-induced oxidative stress, apoptosis, and endothelin-1 secretion dysfunction in mouse IMECs through GLP-1R/PKA and GTPCH1/eNOS signaling pathways.