title: Both triggering and amplifying pathways contribute to fuel-induced insulin secretion in the absence of sulfonylurea receptor-1 in pancreatic beta-cells.
abstract: In normal beta-cells glucose induces insulin secretion by activating both a triggering pathway (closure of K(ATP) channels, depolarization, and rise in cytosolic [Ca(2+)](i)) and an amplifying pathway (augmentation of Ca(2+) efficacy on exocytosis). It is unclear if and how nutrients can regulate insulin secretion by beta-cells lacking K(ATP) channels (Sur1 knockout mice). We compared glucose- and amino acid-induced insulin secretion and [Ca(2+)](i) changes in control and Sur1KO islets. In 1 mm glucose (non-stimulatory for controls), the triggering signal [Ca(2+)](i) was high (loss of regulation) and insulin secretion was stimulated in Sur1KO islets. This "basal" secretion was decreased or increased by imposed changes in [Ca(2+)](i) and was dependent on ATP production, indicating that both triggering and amplifying signals are involved. High glucose stimulated insulin secretion in Sur1KO islets, by an unsuspected, transient increase in [Ca(2+)](i) and a sustained activation of the amplifying pathway. Unlike controls, Sur1KO islets were insensitive to diazoxide and tolbutamide, which rules out effects of either drug at sites other than K(ATP) channels. Amino acids potently increased insulin secretion by Sur1KO islets through both a further electrogenic rise in [Ca(2+)](i) and a metabolism-dependent activation of the amplifying pathway. After sulfonylurea blockade of their K(ATP) channels, control islets qualitatively behaved like Sur1KO islets, but their insulin secretion rate was consistently lower for a similar or even higher [Ca(2+)](i). In conclusion, fuel secretagogues can control insulin secretion in beta-cells without K(ATP) channels, partly by an unsuspected influence on the triggering [Ca(2+)](i) signal and mainly by the modulation of a very effective amplifying pathway.
authors.affiliation: Unité d'Endocrinologie et Métabolisme, University of Louvain Faculty of Medicine UCL 55.30, Ave. Hippocrate 55, B-1200 Brussels, Belgium.
authors.forename: Myriam
authors.initials: M
authors.lastname: Nenquin
authors.forename: Andras
authors.initials: A
authors.lastname: Szollosi
authors.forename: Lydia
authors.initials: L
authors.lastname: Aguilar-Bryan
authors.forename: Joseph
authors.initials: J
authors.lastname: Bryan
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Henquin
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D005089:Exocytosis; D005260:Female; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015221:Potassium Channels / Q000737:chemistry / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug / Q000378:metabolism*; D015398:Signal Transduction; D064233:Sulfonylurea Receptors; D013997:Time Factors; D014044:Tolbutamide / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; C577508:Abcc8 protein, mouse; D000959:Antihypertensive Agents; D007004:Hypoglycemic Agents; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D005973:Glutamine; D000255:Adenosine Triphosphate; D014044:Tolbutamide; D005947:Glucose; D003981:Diazoxide; D002118:Calcium