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Phasic Effects of Glucose, Phospholipase A₂, and Lysophospholipids on Insulin Secretion^*

WILFRED Y. FUJIMOTO and STEWART A. METZ

Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition, University of Washington School of Medicine (W. Y.F.) Seattle, Washington 98195
Departments of Medicine and Pharmacology, University of Colorado Health Science Center and the Veterans Administration Medical Center (S.A.M.) Denver, Colorado 80220

Address all correspondence and requests for reprints to: Dr. Wilfred Y. Fujimoto, Department of Medicine RG-26, University of Washington School of Medicine, Seattle, Washington 98195.

Abstract

Arachidonic acid and lysophospholipids generated by glucose stimulation of phospholipase A2 may be related to the biphasic pattern of insulin secretion. Therefore, we examined the effects of glucose, exogenous phospholipase A₂, lysophospholipids, and pharmacological agents which perturb the reesterification or oxygenation of arachidonic acid in superfused monolayer cultures of neonatal rat islet cells. Nordihydroguaiaretic acid (20 µm), an inhibitor of islet lipoxygenase, significantly decreased phasic glucose-stimulated insulin secretion, especially during phase 1, suggesting that stimulatory lipoxygenase metabolites of arachidonic acid contribute to the effects of glucose stimulation. Treatment with exogenous phospholipase A₂ (10 mU/ml) or melittin (1.0 or 2.0 µg/ml) to generate arachidonic acid and lysophospholipids de novo caused a monophasic release of insulin, followed by a gradual decline in insulin secretion despite the continued presence of these agonists. Conversely, p-hydroxymercuribenzoate (15, 30, and 50 µM), which blocks the reacylation of lysophospholipids with arachidonic acid, evoked a concentration-dependent biphasic stimulation of insulin secretion which was reversible. Lipoxygenase inhibition had no effect upon phase 1 secretion by p-hydroxymercuribenzoate, although it did partially reduce phase 2 secretion. However, lysophosphatidylcholine (50, 75, and 100 µg/ml) also caused a concentrationdependent biphasic stimulation of insulin secretion which resembled that seen with p-hydroxymercuribenzoate, suggesting that lysophospholipids were mediating the effects of p-hydroxymercuribenzoate. We speculate that during glucose stimulation of the islet, the following three phospholipase A₂-initiated changes may be important: 1) generation of lysophospholipid to stimulate directly insulin secretion, 2) generation of arachidonic acid and lipoxygenase-mediated arachidonate metabolites, which positively modulate insulin secretion, and 3) generation of cyclooxygenase-mediated arachidonate metabolites, which negatively modulate insulin secretion. (Endocrinology 120: 175–1757,1987)

Footnotes

^* This work was supported by Grants RR-37, AM-15312, and AM-17047 from the NIH.

Clinical Investigator of the V.A.

Received May 30, 1986.

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