Membrane phospholipid turnover as an intermediary step in insulin secretion. Putative roles of phospholipases in cell signaling.

One or more phospholipases of the C and A2 types exist in rodent islets and may play a pivotal role in the cell signaling cascade culminating in exocytotic insulin release. Phospholipase C generates myo-inositol-1,4,5-trisphosphate, which mobilizes a "pool" of calcium in the endoplasmic reticulum and which may also secondarily facilitate calcium (Ca++) influx from the extracellular space to replenish that pool. Diacylglycerol is also generated by phospholipase C action and activates protein kinase C; it may thereby potentiate the cellular response to elevations in cytosolic free Ca++ concentration. Arachidonic acid may be released during the degradation of diacylglycerol and may also contribute to islet activation. Phospholipase C is activated by glucose, cholinergic agonists, and probably by Ca++ fluxes. Phospholipase A2 action generates arachidonic acid and lysophospholipids. Certain lysophospholipids mobilize cellular Ca++, at least in part from superficial, plasmalemmal stores. Native (unoxygenated) arachidonic acid also has the capability of mobilizing cellular Ca++ from membrane-bound stores; it may, in addition, activate protein kinase C, as suggested by recent indirect studies. The further metabolism of arachidonic acid via lipoxygenase and cyclo-oxygenase appears to provide positive and negative modulation, respectively, of stimulated insulin secretion. Many pieces of the puzzle remain, however, to be supplied. For example, it has not yet been unequivocally demonstrated that phospholipase A2 is activated by physiologic stimuli in intact islets. Furthermore, the absence of truly specific pharmacologic stimulators or inhibitors of these processes currently precludes precise delineation of the respective physiologic roles of each potential mediator in stimulus-secretion coupling. When such roles are elucidated, it can be asked whether the defects in insulin secretion in diabetes mellitus may be due in part to abnormalities in the turnover of beta-cell membrane phospholipids and the generation of intracellular lipid-derived signals.