title: Arachidonic acid signaling is involved in the mechanism of imidazoline-induced KATP channel-independent stimulation of insulin secretion.
abstract: The mechanism by which the novel, pure glucose-dependent insulinotropic, imidazoline derivative BL11282 promotes insulin secretion in pancreatic islets has been investigated. The roles of KATP channels, alpha2-adrenoreceptors, the I1-receptor-phosphatidylcholine-specific phospholipase (PC-PLC) pathway and arachidonic acid signaling in BL11282 potentiation of insulin secretion in pancreatic islets were studied. Using SUR1(-/-) deficient mice, the previous notion that the insulinotropic activity of BL11282 is not related to its interaction with KATP channels was confirmed. Insulinotropic activity of BL11282 was not related to its effect on alpha2-adrenoreceptors, I1-imidazoline receptors or PC-PLC. BL11282 significantly increased [3H]arachidonic acid production. This effect was abolished in the presence of the iPLA2 inhibitor, bromoenol lactone. The data suggest that potentiation of glucose-induced insulin release by BL11282, which is independent of concomitant changes in cytoplasmic free Ca2+ concentration, involves release of arachidonic acid by iPLA2 and its metabolism to epoxyeicosatrienoic acids through the cytochrome P-450 pathway.
authors.affiliation: Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, L1:03, SE-171 76 Stockholm, Sweden.
authors.forename: V V
authors.initials: VV
authors.lastname: Sharoyko
authors.forename: I I
authors.initials: II
authors.lastname: Zaitseva
authors.forename: B
authors.initials: B
authors.lastname: Leibiger
authors.forename: S
authors.initials: S
authors.lastname: Efendić
authors.forename: P O
authors.initials: PO
authors.lastname: Berggren
authors.forename: S V
authors.initials: SV
authors.lastname: Zaitsev
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D054755:Imidazoline Receptors / Q000378:metabolism; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D054086:KATP Channels / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000172:deficiency / Q000235:genetics; D054467:Phospholipases A2 / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D017208:Rats, Wistar; D011955:Receptors, Drug; D015398:Signal Transduction / Q000187:drug effects; D064233:Sulfonylurea Receptors; D010738:Type C Phospholipases / Q000378:metabolism; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; D000317:Adrenergic alpha-Antagonists; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D007093:Imidazoles; D054755:Imidazoline Receptors; D007328:Insulin; D054086:KATP Channels; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D054467:Phospholipases A2; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D010738:Type C Phospholipases; D015016:Yohimbine; C577508:Abcc8 protein, mouse; C577509:Abcc8 protein, rat; C423844:BL 11282; C410887:imidazoline I1 receptors; C105598:phosphatidylcholine-specific phospholipase C