title: Mechanism of prostacyclin-induced potentiation of glucose-induced insulin secretion.
abstract: Arachidonic acid metabolites are crucial mediators of inflammation in diabetes. Although eicosanoids are established modulators of pancreatic β-cell function, the role of prostacyclin (prostaglandin I2) is unknown. Therefore, this study aimed to analyze the role of prostacyclin in β-cell function. Prostacyclin synthase (PGIS) was weakly expressed in rat islet cells but nevertheless significantly increased by incubation with 30 mM glucose, especially in non-β-cells. PGIS was overexpressed in INS1E cells, and the regulation of insulin secretion was analyzed. PGIS overexpression strongly potentiated glucose-induced insulin secretion along with increased insulin content and ATP production. Importantly, overexpression of PGIS potentiated only nutrient-induced insulin secretion. The effect of PGIS overexpression was mediated by prostacyclin released from insulin-secreting cells and dependent on prostacyclin receptor (IP receptor) activation, with concomitant cAMP production. The cAMP-mediated potentiation of glucose-induced insulin secretion by prostacyclin was independent of the protein kinase A pathway but strongly attenuated by the knockdown of the exchange protein directly activated by cAMP 2 (Epac2), pointing to a crucial role for Epac2 in this process. Thus, prostacyclin is a powerful potentiator of glucose-induced insulin secretion. It improves the secretory capacity by inducing insulin biosynthesis and probably by stimulating exocytosis. Our findings open a new therapeutical perspective for an improved treatment of type 2 diabetes.
authors.affiliation: Institute of Clinical Biochemistry, Hannover Medical School, 30623 Hannover, Germany. gurgul-convey.ewa@mh-hannover.de
authors.forename: Ewa
authors.initials: E
authors.lastname: Gurgul-Convey
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Hanzelka
authors.forename: Sigurd
authors.initials: S
authors.lastname: Lenzen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D011464:Epoprostenol / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D034622:RNA Interference; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D007328:Insulin; C486707:Rapgef4 protein, mouse; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D000242:Cyclic AMP; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase; D005947:Glucose