Putative mediators of insulin secretion include calcium, prostaglandins, and cyclic nucleotides. The focus of my reseach is to determine the synthetic profiles of the latter two mediators in isolated islets from rat pancreas, and to determine their participation in the process in insulin secretion. Using homogenates of isolated islets, we are studing not only the synthesis of the primary prostaglandins, but also their metabolism. The biochemical pathways we are investigating include arachidonate metabolism through prostaglandin cyclooxygenase, 15-keto-dehydrogease, and reductase. Evidence for a novel liproxygenase pathways in islet tissue is also being studied. In addition we are comparing the prostaglandin synthesis profile of exocrine tissue (acinar) hemogenates with the profile found in islets. The synthesis of prostaglandins will also be studied in intact islet, as well as in isolated cells from disrupted islets. Various insulin secretogogues will be used to study the response of prostaglandin synthesis and metabolism in islets during stimulation of secretion and/or synthesis. With regard to prostaglandin synthesis, the activity of phospholipase A2 (PLA2) is believed to determine the availability of arachidonic acid for cell prostaglandin synthesis. The activity of PLA2 in insolated islet hemogenates is being assessed, and the effect of insulin secretogogues on enzyme activity is being determined. My previous research has suggested that cyclic guanosine-3',5'-monophosphate (GMP) may play a role in the first-phase release of inslin. A more clear understanding of the dependence of insulin release on cyclic GMP levels in the isolated islet is to be sought, with the view that cyclic nucleotides regulate calcium exchange phenomena and perhaps other cellular biochemical activities. A relationship between the activity of PLA2 and guanylate cyclase activity in intact cells has been an elusive problem, and perhaps cell levels of arachidonic acid or prostaglandins are important factors.
