Involvement of phospholipase A2 and arachidonic acid in cholecystokinin-8-induced insulin secretion in rat islets.
Cholecystokinin (CCK) has been shown to stimulate insulin secretion through an effect which involves mediation by phospholipase C (PLC) and protein kinase C (PKC). However, data exist suggesting involvement also of other transduction pathways. We investigated possible involvement of phospholipase A2 (PLA2) and arachidonic acid (AA) in mechanisms of insulin secretion, induced by the C-terminal octapeptide of CCK (CCK-8) in isolated rat islets. At 5.6 mM glucose, the specific PLA2 inhibitor p-amylcinnamoylantranilic acid (ACA; 50 microM) diminished CCK-8 (100 nM)-stimulated insulin secretion (by 57 +/- 16%; P = 0.001). Furthermore, at 5.6 mM glucose, CCK-8 significantly increased the efflux of [3H]arachidonic acid from prelabelled islets (by 130 +/- 25%; P < 0.001). These results imply that CCK-8 activates PLA2 to form AA in islets. To study whether the insulinotropic effect of CCK-8 is due to AA per se or to its metabolites, the oxidative pathways of the AA metabolism were inhibited. However, the cyclooxygenase inhibitors, indomethacin (30 microM) and salicylate (1.25 mM) as well as the lipoxygenase inhibitors baicalein (1-100 microM) and esculetin (0.5-50 microM), did not affect CCK-8-induced insulin secretion. We conclude that CCK-8-induced insulin secretion is partially mediated by a pathway involving PLA2, and that the formed AA, rather than its metabolites, is of importance.
Simonsson
E
E
Department of Medicine, Lund University, Malmö University Hospital, Sweden. erik.simonsson@medforsk.mas.lu.se
Karlsson
S
S
Ahrén
B
B
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors; D044950:Flavanones; D005419:Flavonoids / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054467:Phospholipases A2; D051381:Rats; D017207:Rats, Sprague-Dawley; D012459:Salicylates / Q000494:pharmacology; D020156:Salicylic Acid; D012844:Sincalide / Q000494:pharmacology*; D014468:Umbelliferones / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D044950:Flavanones; D005419:Flavonoids; D007328:Insulin; D016859:Lipoxygenase Inhibitors; D012459:Salicylates; D014468:Umbelliferones; D016718:Arachidonic Acid; C006680:baicalein; D010741:Phospholipases A; D054467:Phospholipases A2; D005947:Glucose; D012844:Sincalide; D020156:Salicylic Acid; C007628:esculetin; D007213:Indomethacin