1744-P: Exenatide Activates PPARd to Promote Mitochondrial Function for Insulin Secretion in Islet ß-Cells

Aim: Glucagon-like peptide 1 receptor agonists can lower blood glucose by increasing glucose-stimulated insulin secretion (GSIS). However, related molecular mechanisms remain to be further explored.

Methods: C57BL/6J mice were treated with exenatide, GW501516 (GW, a PPARδ agonist) or saline for 8 weeks after a 12-week high-fat diet (HFD) challenge. Phenotypic evaluations were performed during and after the interventions. In vitro, mouse pancreatic β cells (NIT1) were treated with palmitic acid (PA), PA+exendin-4 (Exe), PA+GW, PA+GSK0660 (GSK, a PPARδ antagonist), and PA+GSK+Exe, respectively. PPARδ knockout (KO) NIT1 cells were constructed using CRISPR/Cas9 method. The KO cells were also treated by PA and PA+Exe. After a 24-hour incubation, GSIS tests were performed, and PPARδ expression and mitochondrial function were also detected.

Results: Compared with HFD mice treated with saline, exenatide and GW treatments lowered body weight and fasting blood glucose, improved glucose tolerance and insulin sensitivity. Moreover, normal mitochondrial morphology in pancreatic islets of exenatide and GW treated mice were found with Transmission electron microscopy, while significantly abnormal mitochondria were noted in saline group. In vitro, compared with PA treatment alone, NIT1 cells treated by PA+Exe and PA+GW showed enhanced GSIS, along with increased PPARδ expression, lower ADP/ATP ratio and lactic acid levels, more mitochondrial DNA and higher mitochondrial membrane potential. However, opposite results were found in cells treated with PA+GSK. In addition, in PA+GSK+Exe group, GSK weakened the effects of Exe on GSIS and mitochondrial function. KO cells treated with PA showed similar changes in GSIS and mitochondrial function as PA+GSK treated cells. Importantly, adding Exe couldn’t completely reverse the impairment.

Conclusion: Exenatide protects GSIS function in islet β cells by enhancing mitochondrial function through promoting PPARδ expression.