Signaling and sites of interaction for RX-871024 and sulfonylurea in the stimulation of insulin release

1 The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institute, Karolinska Hospital, S-171 76 Stockholm, Sweden; and 2 Lomonosov Moscow State University, Moscow 19899, Russia 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 (K ATP ) blockers, on insulin secretion and cytoplasmic free calcium concentration ([Ca 2+ ] 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 -cells. At maximal effective concentrations of the compounds, RX-871024 had a more pronounced insulinotropic effect than glibenclamide, but the increase in [Ca 2+ ] 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 K ATP channels and a direct stimulation of exocytosis. At a similar increase in [Ca 2+ ] 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. pancreatic islets; insulin secretion; cytoplasmic free Ca 2+ concentration