title: Group X secretory phospholipase A2 regulates insulin secretion through a cyclooxygenase-2-dependent mechanism.
abstract: Group X secretory phospholipase A2 (GX sPLA2) potently hydrolyzes membrane phospholipids to release arachidonic acid (AA). While AA is an activator of glucose-stimulated insulin secretion (GSIS), its metabolite prostaglandin E2 (PGE2) is a known inhibitor. In this study, we determined that GX sPLA2 is expressed in insulin-producing cells of mouse pancreatic islets and investigated its role in beta cell function. GSIS was measured in vivo in wild-type (WT) and GX sPLA2-deficient (GX KO) mice and ex vivo using pancreatic islets isolated from WT and GX KO mice. GSIS was also assessed in vitro using mouse MIN6 pancreatic beta cells with or without GX sPLA2 overexpression or exogenous addition. GSIS was significantly higher in islets isolated from GX KO mice compared with islets from WT mice. Conversely, GSIS was lower in MIN6 cells overexpressing GX sPLA2 (MIN6-GX) compared with control (MIN6-C) cells. PGE2 production was significantly higher in MIN6-GX cells compared with MIN6-C cells and this was associated with significantly reduced cellular cAMP. The effect of GX sPLA2 on GSIS was abolished when cells were treated with NS398 (a COX-2 inhibitor) or L-798,106 (a PGE2-EP3 receptor antagonist). Consistent with enhanced beta cell function, GX KO mice showed significantly increased plasma insulin levels following glucose challenge and were protected from age-related reductions in GSIS and glucose tolerance compared with WT mice. We conclude that GX sPLA2 plays a previously unrecognized role in negatively regulating pancreatic insulin secretion by augmenting COX-2-dependent PGE2 production.
authors.affiliation: From Saha Cardiovascular Research Center and Departments of Internal Medicine and pshri2@uky.edu.
authors.forename: Preetha
authors.initials: P
authors.lastname: Shridas
authors.affiliation: From Saha Cardiovascular Research Center and Departments of Internal Medicine and.
authors.forename: Lubna
authors.initials: L
authors.lastname: Zahoor
authors.affiliation: From Saha Cardiovascular Research Center and Departments of Internal Medicine and.
authors.forename: Kathy J
authors.initials: KJ
authors.lastname: Forrest
authors.affiliation: From Saha Cardiovascular Research Center and Pharmacology and Nutritional Sciences, Division of Nutritional Sciences, University of Kentucky Medical Center, Lexington Kentucky 40536.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Layne
authors.affiliation: From Saha Cardiovascular Research Center and Pharmacology and Nutritional Sciences, Division of Nutritional Sciences, University of Kentucky Medical Center, Lexington Kentucky 40536.
authors.forename: Nancy R
authors.initials: NR
authors.lastname: Webb
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D054509:Group X Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000378:metabolism; D007515:Islets of Langerhans / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D007328:Insulin; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D054509:Group X Phospholipases A2; D005947:Glucose; D015232:Dinoprostone
keywords: Cyclooxygenase (COX); Insulin Secretion; Pancreatic Islet; Prostaglandin; Type 2 Diabetes