Ether-linked lysophospholipids initiate insulin secretion. Lysophospholipids may mediate effects of phospholipase A2...

Phospholipase A2 activation may be a pivotal step in glucose-induced insulin secretion; however, recent studies have focused on only one by-product (arachidonic acid). To examine the possible role of the other by-product (lysophospholipids), the lysoderivatives of alkylacyl- (ether linked) or diacylphospholipids were applied to rat islets in static incubations. 1-O-alkyl-2-lyso-sn-glyceryl-3-phosphorylcholine [lyso-PAF, the precursor of platelet-activating factor (PAF)] or lysophosphatidylcholine initiated insulin release at 1.7 mM glucose. Two preparations of PAF itself (0.005-5000 ng/ml) were without effect at 1.7 or 16.7 mM glucose, but PAF was nearly equipotent to lyso-PAF at greater than or equal to 20 micrograms/ml. A precursor-product relationship was suggested because the precursors (alkylacyl- or diacylglyceryl-phosphorylcholine) of all three active metabolites were inactive. The stimulatory effect of lyso-PAF is largely independent of any toxic or lytic effect, being biphasic, reversible, unassociated with impairment of the subsequent physiologic functioning of treated islets, and inhibitable (by Ni2+, La3+, or nordihydroguaiaretic acid but not by other lipoxygenase inhibitors). It also occurred at threshold concentrations at which islet morphology and 51Cr retention were preserved. Furthermore, lyso-PAF-induced insulin secretion was markedly impaired by reduced ambient temperature (16 degrees C) or by the impermeant anion isethionate, further implying initiation of true exocytotic granule release and fission. Lyso-PAF (but not arachidonic acid) also circumvented the inhibition of glucose-induced insulin release caused by phospholipase inhibitors. Generation of endogenous lysophospholipids through exogenous application of phospholipase A2 also initiated insulin release, an effect responding to a panel of potential inhibitors identically to that induced by exogenously provided lysophospholipids. We propose that glucose activates phospholipase A2 in the pancreatic islet, leading to the generation of lysophospholipids; the latter may couple energy production to insulin release, at least in part via the promotion of Ca2+ translocation.