Oxygenation products of arachidonic acid: third messengers for insulin release.

Although an association between membrane phospholipid turnover and exocytotic hormone release has long been recognized, a causal relationship has not been firmly established. Recent studies suggest that glucose (and probably other insulin secretagogues) activates phospholipases and thereby releases membrane-bound arachidonic acid (AA). AA is then converted through islet 12-lipoxygenase to mediators or modulators of insulin release (tentatively identified as peroxides and epoxides of arachidonate). These products may be critical links in stimulus-secretion coupling, since blockade of either AA release or lipoxygenation abrogates insulin release induced by glucose and many other (but not all) stimuli. Cogeneration of prostaglandins from AA through the cyclooxygenase pathway may directly or indirectly modulate the formation and/or effect of lipoxygenase products. A critical role for lipoxygenase products (and possibly metabolites of AA synthesized by other pathways, such as P-450-dependent monooxygenases) may extend to many secretory cells in addition to pancreatic beta cells. The phasic release of AA described in many cells could explain the biphasic pattern of insulin release induced by glucose. Since some phospholipases and lipoxygenases are Ca++ activated, the release of AA in conjunction with its oxygenation appears to be a concerted system generating "third messengers" for hormone release.