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

par Louchami, Karim ;Jijakli, Hassan ;Sener, Abdullah ;Malaisse, Willy
Référence Research communications in molecular pathology and pharmacology, 99, 2, page (155-168)
Publication Publié, 1998-02

Article révisé par les pairs

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Résumé :

This study aims at gaining further insight into the mode of action of repaglinide in pancreatic islet B-cells. At a 1.0 μmol/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 μmol/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 μmol/L and a maximal response was reached at 10.0 μmol/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 μmol/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 μmol/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 Ca2+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.