The role of specific metabolism of arachidonic acid (AA) in the regulation of secretion of pancreatic islet hormones is being defined. The focus is on the lipoxygenase, cyclooxygenase and epoxygenase metabolic pathways leading to formation of leukotrienes, prostaglandins and epoxyeicosanoids, respectively. The goal is to prove that these eicosanoids derived from AA in pancreatic islets play a significant modulatory role in secretion of islet hormones. The hypotheses are: 1) individual eicosanoids differ in their ability to influence the release of insulin or glucagon and in combination they exert synergism or antagonism; 2) the net effect of enhanced AA metabolism on secretion of islet hormones is determined by the products formed in and the balance between the individual metabolic pathways; 3) AA metabolites differ in their mechanisms of action in islets, and changes in calcium homeostasis and protein phosphorylation are among these mechanisms; and 4) perturbations in AA metabolism occur due either to nutritional conditions or enzyme defects and contribute to spontaneously abnormal secretion of insulin.
The specific aims, based on these hypotheses, are 1) to define the effects of eicosanoids on islet hormone secretion; 2) to characterize the AA metabolism in islet cells; 3) to characterize the mechanisms of action of AA metabolites on islet hormone secretion; and 4) to search for a role of AA metabolism in abnormal function of islets. To reach the aims, the basic experimental approach will be to use pancreatic islets or pancreata from rats, mice and dogs, some of which have normal and some abnormal islet hormone secretion, and continuously cultured rat insulinoma cell lines, in order to monitor a) islet hormone secretion in response to exogenous AA metabolites, and to nutrients or drugs which perturb endogenous AA metabolism, b) the AA metabolism in the presence of physiological modifiers of islet hormone synthesis and secretion, and c) calcium homeostasis, and phosphorylation of proteins in islet cells at times AA metabolites have been added or endogenous AA metabolism has been perturbed. The new knowledge to be derived should enhance the understanding of the regulation of secretion of islet hormones and provide clues for the aberrations which could cause disease states such as diabetes mellitus.
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