1. Role of lipid peroxidation and PPAR-δ in amplifying glucose-stimulated insulin secretion
- Author
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Cohen, Guy, Riahi, Yael, Shamni, Ofer, Guichardant, Michel, Chatgilialoglu, Chryssostomos, Ferreri, Carla, Kaiser, Nurit, and Sasson, Shlomo
- Subjects
Lipid peroxidation -- Physiological aspects -- Research ,Unsaturated fatty acids -- Physiological aspects -- Research ,Liquid chromatography -- Usage ,Hyperglycemia -- Development and progression -- Research ,Health - Abstract
OBJECTIVE--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. RESEARCH DESIGN AND METHODS--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. RESULTS--High glucose activated [cPLA.sub.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-amplffying effect of high glucose preexposure and of the PPAR-5 agonist GW501516 in INS-1E cells and isolated rat islets. These effects were blocked with GSK0660, a selective PPAR-8 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. CONCLUSIONS--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. Diabetes 60:2830-2842, 2011, The effect of glucose on β-cell function depends on its concentration and duration of exposure (1). An acute exposure to high glucose triggers the classical biphasic insulin secretion as a [...]
- Published
- 2011
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