GLP-1 receptor agonist protects glucose-stimulated insulin secretion in pancreatic β-cells against lipotoxicity via PPARδ/UCP2 pathway

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) enhance glucose-stimulated Insulin secretion (GSIS). Peroxisome Proliferator-activated Receptor δ (PPARδ) plays an essential role in mitochondrial function and glucose homeostasis. This study investigated the role of PPARδ in the protective effects of GLP-1RAs on pancreatic β-cells against lipotoxicity. C57BL/6J mice fed a high-fat diet (HFD) for 12 weeks were treated with exenatide (Exe), GW501516 (GW, a PPARδ Agonist), saline, or dimethyl sulfoxide (DM) for 8 weeks, followed by phenotypic assessments. In vitro, mouse pancreatic β-cells (NIT-1 cells) were exposed to palmitic acid (PA), PA + exendin-4 (Ex-4), PA + GW, PA + GSK0660 (GSK, a PPARδ antagonist), or PA + Ex-4 + GSK. Compared to HFD mice treated with saline or DM, Exe and GW administration reduced fasting blood glucose, enhanced Insulin secretion function and glucose tolerance, and upregulated PPARδ expression. NIT-1 cells treated with PA + Ex-4 and PA + GW showed enhanced GSIS capacity, increased PPARδ expression, decreased UCP2 expression and ADP/ATP ratio, and improved mitochondrial DNA content and mitochondrial membrane potential compared with those treated with PA alone, whereas the opposite results were observed in the PA + GSK group. In the PA + Ex-4 + GSK group, GSK attenuated the effects of Ex-4. PPARδ-knockout (KO) cells treated with PA exhibited similar changes to those treated with PA + GSK, and Ex-4 did not reverse these alterations. Moreover, Ex-4 failed to reverse mitochondrial function or GSIS in pancreatic β-cells with UCP2 overexpression despite an increase in PPARδ expression. Thus, GLP-1RA Exe/Ex-4 preserved GSIS against lipotoxicity in pancreatic β-cells by modulating mitochondrial function through the PPARδ/UCP2 axis.

Glucagon-like peptide 1 receptor agonists; Glucose-stimulated insulin secretion; Mitochondrial function; Peroxisome proliferator-activated receptor δ; Uncoupling protein 2.