Effect of repaglinide upon nutrient metabolism, biosynthetic activity, cationic fluxes and insulin release in rat pancreatic islets

Abstract

This study aims at gaining further insight into the mode of action of repaglinide in pancreatic islet B-cells. At a 1.0 mumol/L concentration, the meglitinide analog failed to affect the metabolism of exogenous D-glucose and that of endogenous nutrients in islets prelabeled with either L-[U-14C]glutamine or [U-14C]palmitate. Likewise, repaglinide (1.0 mumol/L) failed to modify significantly the incorporation of L-[4-3H]phenylalanine into TCA-precipitable material in islets exposed to a close-to-physiological concentration of D-glucose (7.0 mmol/L). The threshold concentration for the insulinotropic action of repaglinide was close to 0.1-1.0 mumol/L and a maximal response was reached at 10.0 mumol/L in islets incubated in the presence of 5.6-8.3 mmol/L D-glucose. At a higher hexose concentration (16.7 mmol/L), however, an enhancing action of repaglinide (10 mumol/L) upon glucose-stimulated insulin release was only observed over 25 min stimulation in perifused islets, no significant increase in insulin output being detected when islets were exposed to repaglinide (0.1 mumol/L to 0.1 mmol/L) over 90 min incubation at the high D-glucose level. The increase in insulin output evoked by repaglinide in the islets perifused at 16.7 mmol/L D-glucose coincided with a modest increase in 86Rb outflow and a marked stimulation of 45Ca efflux from prelabeled islets, suggesting stimulation of Ca2+ influx into the islet cells and subsequent activation of Ca(2+)-responsive K+ channels. When the administration of repaglinide was halted, the reversibility of its cationic and secretory effects was more pronounced in islets perifused at a high (16.7 mmol/L), rather than a low (6.0 mmol/L), D-glucose concentration. These findings support the view that the primary site of action of repaglinide consists in a remodeling of cationic fluxes, and document that this drug displays favorable attributes as an insulinotropic agent for the treatment of non-insulin-dependent diabetes, such as its lack of interference with nutrient metabolism and biosynthetic activity in isolated islets, the low threshold concentration for its insulin-releasing action and its capacity to augment, at least transiently, insulin release at a high concentration of D-glucose.