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Role of lipid peroxidation and PPAR-δ in amplifying glucose-stimulated insulin secretion.

Cohen G, Riahi Y, Shamni O, Guichardant M, Chatgilialoglu C, Ferreri C, Kaiser N, Sasson S - Diabetes (2011)

Bottom Line: 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.Cytotoxic effects of 4-HNE were observed only above the physiologically effective concentration range.This molecule is an endogenous ligand for PPAR-δ, which amplifies insulin secretion in β-cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, School of Pharmacy, Faculty of Medicine, Institute for Drug Research, Hebrew University, Jerusalem, Israel.

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(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.

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.

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Related in: MedlinePlus

A model for the dual function of 4-HNE in β-cells. Exposure to high glucose markedly enhances ROS production as well as the activation of cPLA2 in β-cells by inducing Ser505 and Ser515 phosphorylations and the subsequent release of arachidonic acid (ARA) and linoleic acid (LNA) from phospholipids. ROS-mediated peroxidation of these PUFAs results in the generation of 4-HNE. This molecule affects β-cell function in two major ways; when present at nontoxic concentrations, it amplifies insulin secretion in a PPAR-δ–RXR–dependent manner. RXR is activated by cis-retinoic acid (cRA). However, chronic hyperglycemia may lead to an excessive generation of 4-HNE with the accumulation of 4-HNE adducts, causing β-cell dysfunction, characteristic of the advanced stages of type 2 diabetes. (A high-quality color representation of this figure is available in the online issue.)
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Figure 8: A model for the dual function of 4-HNE in β-cells. Exposure to high glucose markedly enhances ROS production as well as the activation of cPLA2 in β-cells by inducing Ser505 and Ser515 phosphorylations and the subsequent release of arachidonic acid (ARA) and linoleic acid (LNA) from phospholipids. ROS-mediated peroxidation of these PUFAs results in the generation of 4-HNE. This molecule affects β-cell function in two major ways; when present at nontoxic concentrations, it amplifies insulin secretion in a PPAR-δ–RXR–dependent manner. RXR is activated by cis-retinoic acid (cRA). However, chronic hyperglycemia may lead to an excessive generation of 4-HNE with the accumulation of 4-HNE adducts, causing β-cell dysfunction, characteristic of the advanced stages of type 2 diabetes. (A high-quality color representation of this figure is available in the online issue.)

Mentions: Chronic high glucose-induced β-cell dysfunction may be associated with an excessive generation of 4-hydroxyalkenals, which are deleterious to cells. Of interest is the finding that increased LO activity induces β-cell dysfunction (50). Whether this results in an excessive production of hydroperoxy metabolites of AA and LA, which are subsequently peroxidized to cytotoxic levels of 4-HNE, remains to be investigated. Finally, our findings on glucose-mediated generation of 4-HNE and the subsequent activation of PPAR-δ that leads to an amplified insulin secretion from β-cells are summarized in the model shown in Fig. 8.


Role of lipid peroxidation and PPAR-δ in amplifying glucose-stimulated insulin secretion.

Cohen G, Riahi Y, Shamni O, Guichardant M, Chatgilialoglu C, Ferreri C, Kaiser N, Sasson S - Diabetes (2011)

A model for the dual function of 4-HNE in β-cells. Exposure to high glucose markedly enhances ROS production as well as the activation of cPLA2 in β-cells by inducing Ser505 and Ser515 phosphorylations and the subsequent release of arachidonic acid (ARA) and linoleic acid (LNA) from phospholipids. ROS-mediated peroxidation of these PUFAs results in the generation of 4-HNE. This molecule affects β-cell function in two major ways; when present at nontoxic concentrations, it amplifies insulin secretion in a PPAR-δ–RXR–dependent manner. RXR is activated by cis-retinoic acid (cRA). However, chronic hyperglycemia may lead to an excessive generation of 4-HNE with the accumulation of 4-HNE adducts, causing β-cell dysfunction, characteristic of the advanced stages of type 2 diabetes. (A high-quality color representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198069&req=5

Figure 8: A model for the dual function of 4-HNE in β-cells. Exposure to high glucose markedly enhances ROS production as well as the activation of cPLA2 in β-cells by inducing Ser505 and Ser515 phosphorylations and the subsequent release of arachidonic acid (ARA) and linoleic acid (LNA) from phospholipids. ROS-mediated peroxidation of these PUFAs results in the generation of 4-HNE. This molecule affects β-cell function in two major ways; when present at nontoxic concentrations, it amplifies insulin secretion in a PPAR-δ–RXR–dependent manner. RXR is activated by cis-retinoic acid (cRA). However, chronic hyperglycemia may lead to an excessive generation of 4-HNE with the accumulation of 4-HNE adducts, causing β-cell dysfunction, characteristic of the advanced stages of type 2 diabetes. (A high-quality color representation of this figure is available in the online issue.)
Mentions: Chronic high glucose-induced β-cell dysfunction may be associated with an excessive generation of 4-hydroxyalkenals, which are deleterious to cells. Of interest is the finding that increased LO activity induces β-cell dysfunction (50). Whether this results in an excessive production of hydroperoxy metabolites of AA and LA, which are subsequently peroxidized to cytotoxic levels of 4-HNE, remains to be investigated. Finally, our findings on glucose-mediated generation of 4-HNE and the subsequent activation of PPAR-δ that leads to an amplified insulin secretion from β-cells are summarized in the model shown in Fig. 8.

Bottom Line: 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.Cytotoxic effects of 4-HNE were observed only above the physiologically effective concentration range.This molecule is an endogenous ligand for PPAR-δ, which amplifies insulin secretion in β-cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, School of Pharmacy, Faculty of Medicine, Institute for Drug Research, Hebrew University, Jerusalem, Israel.

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(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.

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.

Show MeSH
Related in: MedlinePlus