A role for the lipoxygenase pathway of arachidonic acid metabolism in glucose- and glucagon-induced insulin secretion.

Although the cyclo-oxygenase pathway of arachidonic acid (AA) metabolism inhibits glucose-stimulated insulin release through synthesis of prostaglandins, very little attention has been given to the effects of lipoxygenase pathway products on beta cell function. We have examined the effects of two structurally-dissimilar lipoxygenase inhibitors on insulin release from monolayer-cultured rat islet cells. Both nordihydroguaiaretic acid (NDGA, 20-50 microM) and BW755c (100-250 microM) caused a dose-responsive inhibition of glucose-induced insulin release. This inhibitory effect occurred despite concomitant inhibition of prostaglandin E synthesis. Lipoxygenase inhibitors also impeded cyclic AMP accumulation. Insulin and cyclic AMP release induced by glucagon were also blunted. These studies suggest the hypothesis that AA released in or near the beta cell is metabolized to lipoxygenase product(s) which have feed-forward properties important to glucose- and glucagon-stimulated cyclic nucleotide accumulation and insulin release.