Disopyramide and its metabolite enhance insulin release from clonal pancreatic beta-cells by blocking K(ATP) channels.

Abstract

In an insulin-secreting pancreatic beta-cell line (MIN6), insulin release was caused by disopyramide, an antiarrhythmic drug with Na-channel blocking action, and its main metabolite mono-isopropyl disopyramide (MIP). Insulin secretion, measured as immunoreactive insulin (IRI), was accelerated to 265.7% of the control by disopyramide and to 184.4% by MIP, with half-effective concentrations (EC50) of 30.9 +/- 1.5 microM and 92.4 +/- 2.2 microM. We tested the possibility that these drugs induce insulin release by inhibiting ATP-sensitive K+ (K(ATP)) channels of MIN6 cells. In the cell-attached or ATP-free inside-out mode with patch membranes on MIN6 cells, K-selective channels were recorded with unitary conductance of 70.5 +/- 3.5 pS (150 mM external K+ ions at room temperature). The channels were concluded to be MIN6-K(ATP) channels because they were closed by extracellular high glucose (11.0 mM) or glibenclamide (200 nM) and were reversibly activated by diazoxide (50 microM). In the inside-out patch mode, they were inhibited by micromolar ATP. In both cell-attached and insideout mode, disopyramide and MIP inhibited single MIN6-K(ATP) channels. In the inside-out mode, they produced a dose-dependent inhibition of channel activity: the half-blocking concentrations (IC50) were 4.8 +/- 0.2 microM for disopyramide and 40.4 +/- 3.1 microM for MIP. It was therefore concluded that both agents exert insulinotrphic effect through the inhibition of membrane K(ATP) channels in MIN6 cells.