title: Signaling and sites of interaction for RX-871024 and sulfonylurea in the stimulation of insulin release.
abstract: The objective of this study was to compare effects of RX-871024, a compound with imidazoline structure, and the sulfonylurea glibenclamide, representatives of two groups of ATP-dependent potassium channel (KATP) blockers, on insulin secretion and cytoplasmic free calcium concentration ([Ca2+]i). Furthermore, we studied the interaction of the compounds on these two parameters. The experiments were performed in the perfused rat pancreas, isolated rat pancreatic islets, and dispersed beta-cells. At maximal effective concentrations of the compounds, RX-871024 had a more pronounced insulinotropic effect than glibenclamide, but the increase in [Ca2+]i was similar. Glibenclamide enhanced the insulinotropic effect of suboptimal concentrations of RX-871024 at 3.3 and 16.7 mM glucose. Notably, glibenclamide and RX-871024 also stimulated insulin secretion under Ca(2+)-clamped conditions, i.e., during plasma membrane depolarization with KCl and glucose or in permeabilized islets. The magnitudes of insulin stimulation under the latter types of conditions were similar for both compounds. It is concluded that RX-871024 and the sulfonylurea glibenclamide promote insulin secretion by two mechanisms, namely closure of KATP channels and a direct stimulation of exocytosis. At a similar increase in [Ca2+]i, the maximal stimulatory effect of RX-871024 on insulin secretion was stronger than that of glibenclamide, implying that RX-871024 also affects insulin secretion by a signal transduction pathway that is not activated by glibenclamide.
authors.affiliation: Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden.
authors.forename: A M
authors.initials: AM
authors.lastname: Efanov
authors.forename: S V
authors.initials: SV
authors.lastname: Zaitsev
authors.forename: I B
authors.initials: IB
authors.lastname: Efanova
authors.forename: S
authors.initials: S
authors.lastname: Zhu
authors.forename: C G
authors.initials: CG
authors.lastname: Ostenson
authors.forename: P O
authors.initials: PO
authors.lastname: Berggren
authors.forename: S
authors.initials: S
authors.lastname: Efendić
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005947:Glucose / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D009994:Osmolar Concentration; D010179:Pancreas / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D013453:Sulfonylurea Compounds / Q000494:pharmacology*
chemical_list: C101943:2-(2-imidazolin-2-yl)-1-phenyl-1H-indole; D007093:Imidazoles; D007211:Indoles; D007328:Insulin; D013453:Sulfonylurea Compounds; D005947:Glucose; D005905:Glyburide; D002118:Calcium