title: 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.
authors.affiliation: Laboratory of Experimental Medicine, Brussels Free University, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Louchami
authors.forename: H
authors.initials: H
authors.lastname: Jijakli
authors.forename: A
authors.initials: A
authors.lastname: Sener
authors.forename: W J
authors.initials: WJ
authors.lastname: Malaisse
mesh_terms: D000818:Animals; D002132:Calcium Radioisotopes / Q000378:metabolism; D002219:Carbamates / Q000494:pharmacology*; D002412:Cations / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D019308:Palmitic Acid / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012414:Rubidium Radioisotopes / Q000378:metabolism
chemical_list: D002132:Calcium Radioisotopes; D002219:Carbamates; D002412:Cations; D007004:Hypoglycemic Agents; D007328:Insulin; D010880:Piperidines; D012414:Rubidium Radioisotopes; D005973:Glutamine; D019308:Palmitic Acid; C072379:repaglinide; D005947:Glucose