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The Role of Arachidonic Acid and Its Metabolites in Insulin Secretion From Human Islets of Langerhans

¹ Beta Cell Development and Function Group, Division of Reproductive Health, Endocrinology, and Development, King’s College London, London, U.K
² Division of Immunology and Endocrinology, National Institute for Biological Standards and Control, South Mimms, Hertfordshire, U.K
³ Division of Gene and Cell Based Therapy, King’s College London, London, U.K

Address correspondence and reprint requests to Dr. S.J. Persaud, 2.9N Hodgkin Building, King’s College London, London SE1 1UL, U.K. E-mail: shanta.persaud{at}kcl.ac.uk

Abbreviations: AACOCF₃, arachidonyltrifluoromethyl ketone; baicalein, 5,6,7-trihydroxyflavone; cPLA₂, cytosolic phospholipase A₂; COX, cyclooxygenase; HETE, hydroxyeicosatetraenoic acid; LOX, lipoxygenase; NS-398, N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; PACOCF₃, palmityltrifluoromethylketone; PGE₂, prostaglandin E₂; phenidone, 1-phenyl-3-pyrazolidinone

The roles played by arachidonic acid and its cyclooxygenase (COX)-generated and lipoxygenase (LOX)-generated metabolites have been studied using rodent islets and insulin-secreting cell lines, but very little is known about COX and LOX isoform expression and the effects of modulation of arachidonic acid generation and metabolism in human islets. We have used RT-PCR to identify mRNAs for cytosolic phospholipase A₂ (cPLA₂), COX-1, COX-2, 5-LOX, and 12-LOX in isolated human islets. COX-3 and 15-LOX were not expressed by human islets. Perifusion experiments with human islets indicated that PLA₂ inhibition inhibited glucose-stimulated insulin secretion, whereas inhibitors of COX-2 and 12-LOX enzymes enhanced basal insulin secretion and also secretory responses induced by 20 mmol/l glucose or by 50 µmol/l arachidonic acid. Inhibition of COX-1 with 100 µmol/l acetaminophen did not significantly affect glucose-stimulated insulin secretion. These data indicate that the stimulation of insulin secretion from human islets in response to arachidonic acid does not require its metabolism through COX-2 and 5-/12-LOX pathways. The products of COX-2 and LOX activities have been implicated in cytokine-mediated damage of ß-cells, so selective inhibitors of these enzymes would be expected to have a dual protective role in diabetes: they would minimize ß-cell dysfunction while maintaining insulin secretion through enhancing endogenous arachidonic acid levels.

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