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- Title
Role of lipid peroxidation and PPAR-δ in amplifying glucose-stimulated insulin secretion.
- Authors
Cohen G; Riahi Y; Shamni O; Guichardant M; Chatgilialoglu C; Ferreri C; Kaiser N; Sasson S; Cohen, Guy; Riahi, Yael; Shamni, Ofer; Guichardant, Michel; Chatgilialoglu, Chryssostomos; Ferreri, Carla; Kaiser, Nurit; Sasson, Shlomo
- Abstract
<bold>Objective: </bold>Previous studies show that polyunsaturated fatty acids (PUFAs) increase the insulin secretory capacity of pancreatic β-cells. We aimed at identifying PUFA-derived mediators and their cellular targets that are involved in the amplification of insulin release from β-cells preexposed to high glucose levels.<bold>Research Design and Methods: </bold>The content of fatty acids in phospholipids of INS-1E β-cells was determined by lipidomics analysis. High-performance liquid chromatography was used to identify peroxidation products in β-cell cultures. Static and dynamic glucose-stimulated insulin secretion (GSIS) assays were performed on isolated rat islets and/or INS-1E cells. The function of peroxisome proliferator-activated receptor-δ (PPAR-δ) in regulating insulin secretion was investigated using pharmacological agents and gene expression manipulations.<bold>Results: </bold>High glucose activated cPLA(2) and, subsequently, the hydrolysis of arachidonic and linoleic acid (AA and LA, respectively) from phospholipids in INS-1E cells. Glucose also increased the level of reactive oxygen species, which promoted the peroxidation of these PUFAs to generate 4-hydroxy-2E-nonenal (4-HNE). The latter mimicked the GSIS-amplifying effect of high glucose preexposure and of the PPAR-δ agonist GW501516 in INS-1E cells and isolated rat islets. These effects were blocked with GSK0660, a selective PPAR-δ antagonist, and the antioxidant N-acetylcysteine or by silencing PPAR-δ expression. High glucose, 4-HNE, and GW501516 also induced luciferase expression in a PPAR-δ-mediated transactivation assay. Cytotoxic effects of 4-HNE were observed only above the physiologically effective concentration range.<bold>Conclusions: </bold>Elevated glucose levels augment the release of AA and LA from phospholipids and their peroxidation to 4-HNE in β-cells. This molecule is an endogenous ligand for PPAR-δ, which amplifies insulin secretion in β-cells.
- Publication
Diabetes, 2011, Vol 60, Issue 11, p2830
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db11-0347