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

Abstract

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 14 CO 2 production from islets prelabelled with either l-[U- 14 C ]glutamine or [U- 14 C ]palmitate. BTS 67 582 (0.1 mM) also failed to affect biosynthetic activity in islets incubated with l-[4- 3 H ]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 45 Ca net uptake. In perifused islets deprived of extracellular d-glucose for 45 min, BTS 67 582 (0.1 mM) decreased 86 Rb outflow from prelabelled islets, but failed to increase 45 Ca efflux and insulin release. In the presence of d-glucose (7.0 mM), BTS 67 582, whilst failing to decrease 86 Rb + outflow, provoked rapid, sustained and rapidly reversible increases of both 45 Ca 2+ efflux and insulin output. The latter increases were attenuated, but not totally suppressed, in the absence of extracellular Ca 2+. 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 Ca 2+ ions may also participate, however, to the islet functional response to BTS 67 582.