Treatment of isolated, perifused rat islets with exogenous PLA2 in amounts ranging from 1 to 1000 mU/ml caused a dose-dependent increase in the rate of insulin secretion. This effect of PLA2 was rapid and seen in the absence of added exogenous fuel. It differed from glucose-induced insulin release in temporal pattern: high concentrations of PLA2 caused a single phase of secretion, and high levels of glucose caused a biphasic pattern of secretion. Like glucose-induced release, PLA2-induced release was partially dependent on extracellular calcium because D600 caused a significant inhibition of release induced by PLA2 at 5 mU/ml. Concentrations of BW755c and NDGA, inhibitors of both the cyclooxygenase and lipoxygenase or only the lipoxygenase pathways of arachidonic acid metabolism, which completely blocked the insulin secretory response to 10 mM glucose, had no effect on the secretory response to 5 mU/ml of PLA2. These inhibitors also inhibited glucose usage by the islets. Finally, although repeated brief exposure of islets to stimulatory concentrations of glucose lead to a progressive increase in the magnitude of both the first and second phases of insulin secretion, repeated brief exposures to PLA2 lead to a progressive decrease in response to each new exposure. Nonetheless, those islets that had been exposed several times to exogenous PLA2, and no longer displayed a response to a further PLA2 exposure, responded normally to the addition of 10 mM glucose. These results indicate that PLA2 is a potent insulin secretagogue, that it shares some of the characteristics of glucose as a secretagogue, but that in many significant ways differs markedly from glucose in its effects on insulin release from isolated islets.

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