Effect of 1,1-dimethyl-2-[2-morpholinophenyl]guanidine fumarate on pancreatic islet function

The modality of the insulinotropic action of 1,1-dimethyl-2-[2-morpholinophenyl]guanidine fumarate (BTS 67 582), a new antidiabetic agent, was investigated in rat pancreatic islets. At a 0.1 mM concentration, which was sufficient to cause a close-to-maximal secretory response, BTS 67 582 failed to affect the utilization and oxidation of exogenous D-glucose, but slightly augmented 14CO2 production from islets prelabelled with either L-[U-14C]glutamine or [U-14C]palmitate. BTS 67 582 (0.1 mM) also failed to affect biosynthetic activity in islets incubated with L-[4-3H]phenylalanine. It augmented Insulin release from islets incubated for 90 min in the absence or presence of D-glucose (2.8 to 16.7 mM), this coinciding with stimulation of 45Ca net uptake. In perifused islets deprived of extracellular D-glucose for 45 min, BTS 67 582 (0.1 mM) decreased 86Rb outflow from prelabelled islets, but failed to increase 45Ca efflux and Insulin release. In the presence of D-glucose (7.0 mM), BTS 67 582, whilst failing to decrease 86Rb+ outflow, provoked rapid, sustained and rapidly reversible increases of both 45Ca2+ efflux and Insulin output. The latter increases were attenuated, but not totally suppressed, in the absence of extracellular Ca2+. BTS 67 582 (0.1 mM) suppressed the inhibitory action of diazoxide (0.25 mM) upon glucose-stimulated Insulin release, but nevertheless augmented Insulin output from islets incubated in the presence of 90 mM K+. These findings support the view that the insulinotropic action of BTS 67 582 is mainly attributable to the inactivation of ATP-sensitive K+ channels. An intracellular redistribution of Ca2+ ions may also participate, however, to the islet functional response to BTS 67 582.