Inhibition of Arachidonate Release by Secretagogue-Stimulated Pancreatic Islets Suppresses both Insulin Secretion and the Rise in β-Cell Cytosolic Calcium Ion Concentration

Sasanka Ramanadham, Richard W. Gross, Xianlin Han, John Turk

Research output: Contribution to journalArticlepeer-review

119 Scopus citations

Abstract

Fuel secretagogues induce hydrolysis of esterified arachidonic acid from pancreatic islet cell phospholipids and accumulation of nonesterified arachidonate at concentrations up to 35 μM. Exogenous arachidonate (5-30 μM) amplifies depolarization-induced insulin secretion from islets. Fuel secretagogueinduced hydrolysis of arachidonate from islet phospholipids occurs in Ca2+-free medium, suggesting the possible involvement of a Ca2+-independent phospholipase. In the companion paper [Gross et al. (1993) Biochemistry (preceding paper in this issue)], we demonstrated that the major islet phospholipase A2 is Ca2+-independent, ATP-stimulated, and inhibited by the haloenol lactone suicide substrate (HELSS) (E)- 6-(bromomethylene)-3-(1-naphthalenyl)-2H-tetrahydropyran-2-one. Here we demonstrate that HELSS suppressed both release of the arachidonate metabolite prostaglandin E2 and insulin secretion from islets stimulated with d-glucose and the muscarinic agonist carbachol. Both prostaglandin E2 release and insulin secretion were suppressed with similar concentration profiles and time courses. Islet oxidation of [14C]- glucose to [14C]CO2, activities of islet lactate dehydrogenase and alanine and aspartate aminotransferases, and carbachol-induced inositol phosphate accumulation in islets were all unaffected by HELSS. Depolarization of isolated β-cells with 40mM KCl induced a rise in cytosolic [Ca2+] that was also unaffected by HELSS. In contrast, the 17 mM d-glucose-induced rise in β-cell [Ca2+] was inhibited by HELSS in a concentration-dependent manner, but that induced by exogenous arachidonate (15 μM) was not. These results suggest that fuel secretagogues activate the islet Ca2+-independent phospholipase A2, resulting in release of nonesterified arachidonate, which facilitates Ca2+ entry into β-cells and promotes insulin secretion.

Original languageEnglish (US)
Pages (from-to)337-346
Number of pages10
JournalBiochemistry
Volume32
Issue number1
DOIs
StatePublished - Jan 1 1993
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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