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

ABSTRACT: OBJECTIVE:Previous studies show that polyunsaturated fatty acids (PUFAs) increase the insulin secretory capacity of pancreatic ?-cells. We aimed at identifying PUFA-derived mediators and their cellular targets that are involved in the amplification of insulin release from ?-cells preexposed to high glucose levels. RESEARCH DESIGN AND METHODS:The content of fatty acids in phospholipids of INS-1E ?-cells was determined by lipidomics analysis. High-performance liquid chromatography was used to identify peroxidation products in ?-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-? (PPAR-?) 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-? agonist GW501516 in INS-1E cells and isolated rat islets. These effects were blocked with GSK0660, a selective PPAR-? antagonist, and the antioxidant N-acetylcysteine or by silencing PPAR-? expression. High glucose, 4-HNE, and GW501516 also induced luciferase expression in a PPAR-?-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 ?-cells. This molecule is an endogenous ligand for PPAR-?, which amplifies insulin secretion in ?-cells.

SUBMITTER: Cohen G

PROVIDER: S-EPMC3198069 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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

Cohen Guy G Riahi Yael Y Shamni Ofer O Guichardant Michel M Chatgilialoglu Chryssostomos C Ferreri Carla C Kaiser Nurit N Sasson Shlomo S

Diabetes 20110906 11

<h4>Objective</h4>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.<h4>Research design and methods</h4>The content of fatty acids in phospholipids of INS-1E β-cells was determined by lipidomics analysis. High-performance liquid chromatography w ...[more]

PMID: 21896929

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Project description:For glucose-stimulated insulin secretion (GSIS) by pancreatic β-cells in animals, it is believed that ATP generated from glucose metabolism is primarily responsible. However, this ignores two well-established aspects in literature: (a) intracellular ATP generation from other sources resulting in an overall pool of ATP, regardless of the original source, and (b) that intracellular glucose transport is 10- to 100-fold higher than intracellular glucose phosphorylation in β-cells. The latter especially provides an earlier unaddressed, but highly appealing, observation pertaining to (at least transient) the presence of intracellular glucose molecules. Could these intracellular glucose molecules be responsible for the specificity of GSIS to glucose (instead of the widely believed ATP production from its metabolism)? In this work, we provide a comprehensive compilation of literature on glucose and GSIS using various cellular systems - all studies focus only on the extracellular role of glucose in GSIS. Further, we carried out a comprehensive analysis of differential gene expression in Mouse Insulinoma 6 (MIN6) cells, exposed to low and high extracellular glucose concentrations (EGC), from the existing whole transcriptome data. The expression of other genes involved in glycolysis, Krebs cycle, and electron transport chain was found to be unaffected by EGC, except Gapdh, Atp6v0a4, and Cox20. Remarkably, 3 upregulated genes (Atp6v0a4, Cacnb4, Kif11) in high EGC were identified to have an association with cellular secretion. Using glucose as a possible ligand for the 3 proteins, computational investigations were carried out (that will require future 'wet validation', both in vitro and in vivo, e.g., using primary islets and animal models). The glucose-affinity/binding scores (in kcal/mol) obtained were also compared with glucose binding scores for positive controls (GCK and GLUT2), along with negative controls (RPA1, KU70-80, POLA1, ACAA1A, POLR1A). The binding affinity scores of glucose molecules for the 3 proteins were found to be closer to positive controls. Therefore, we report the glucose binding ability of 3 secretion-related proteins and a possible direct role of intracellular glucose molecules in GSIS.

Project description:UnlabelledLow-grade inflammation is seen with obesity and is suggested to be a mediator of insulin resistance. The eliciting factor of low-grade inflammation is unknown but increased permeability of gut bacteria-derived lipopolysaccharides (LPS) resulting in endotoxemia could be a candidate. Here we test the effect of LPS and the anti-inflammatory compound resveratrol on glucose homeostasis, insulin levels and inflammation. Mice were subcutaneously implanted with osmotic mini pumps infusing either low-dose LPS or saline for 28 days. Half of the mice were treated with resveratrol delivered through the diet. LPS caused increased inflammation of the liver and adipose tissue (epididymal and subcutaneous) together with enlarged spleens and increased number of leukocytes in the blood. Resveratrol specifically reduced the inflammatory status in epididymal fat (reduced expression of TNFa and Il1b, whereas the increased macrophage infiltration was unaltered) without affecting the other tissues investigated. By LC-MS, we were able to quantitate resveratrol metabolites in epididymal but not subcutaneous adipose tissue. LPS induced insulin resistance as the glucose-stimulated insulin secretion during an oral glucose tolerance test was increased despite similar plasma glucose level resulting in an increase in the insulinogenic index (IGI; delta0-15insulin/delta0-15glucose) from 13.73 to 22.40 pmol/mmol (P < 0.001). This aberration in insulin and glucose homeostasis was normalized by resveratrol.In conclusionLow-dose LPS enhanced the glucose-stimulated insulin secretion without affecting the blood glucose suggesting increased insulin resistance. Resveratrol restored LPS-induced alteration of the insulin secretion and demonstrated anti-inflammatory effects specifically in epididymal adipose tissue possibly due to preferential accumulation of resveratrol metabolites pointing towards a possible important involvement of this tissue for the effects on insulin resistance and insulin secretion.

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

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

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