Although the cylo-oxygenase pathway of arachidonic acid (AA) metabolism inhibits glucose-stimulatedinsulin release throught 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 mono-layer-cultured rat islet cell. Both nordihydroguaiaretic acid (NDGA, 20-50 μM) and BW755c (100-250μM) 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.
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The authors gratefully acknowledge the excellent technical assistance of Ms. 3eanette Teague, Ms. Lytian Fuller, and Mr. David Federighi. This work was supportedb y the Veterans Administrationa, grant from the Upjohn Company, and grants AM-15312 and AM-17847 from the National Instituteso f Health.