Bumetanide reduces insulin release by a direct effect on the pancreatic beta-cells

The effect of the loop diuretic bumetanide on glucose-induced insulin release, 45Ca2+ uptake, 36Cl- fluxes and 86Rb+ (K+ analogue) efflux was tested in isolated beta-cell-rich mouse pancreatic islets. Low concentrations of bumetanide (0.1-10 microM) reduced glucose-induced insulin release as well as 45Ca2+ uptake. High concentrations (0.5-1 mM) augmented glucose-induced insulin release and an intermediate concentration (100 microM) had no effect. Bumetanide (0.01-1 mM) reduced the islet accumulation of 36Cl-. The net efflux of 36Cl- in the presence of 20 mM D-glucose was reduced by a concentration (10 microM) that lowered glucose-induced insulin release. Bumetanide (10 microM) did not affect the rate coefficient for 36Cl- efflux, which suggests that chloride permeability is not affected. Bumetanide (10 microM) reduced 86Rb+ efflux from preloaded islets. The data show that bumetanide reduces insulin release by a direct effect on pancreatic beta-cells and suggest that this may be due to reduced chloride accumulation by a Na+, K+, Cl- co-transport system. It is suggested that the reduced chloride level is responsible for the decrease in glucose-induced chloride efflux and insulin release.