Insulinotropic action of meglitinide analogues: modulation by an activator of ATP-sensitive K+ channels and high extracellular K+ concentrations.
At normal extracellular K+ concentration (5 mM), the meglitinide analogues A-4166, KAD-1229, repaglinide and S3075, all tested at a 10 mu M concentration, markedly enhanced insulin release evoked by 6 mM D-glucose in isolated rat pancreatic islets. They failed, however, to augment the much higher rate of insulin release evoked by D-glucose in islets exposed to a high K+ concentration (30 mM). Under the latter conditions, the potent diazoxide analogue BPDZ-44 (50 mu M) did not exert any sizeable effect upon insulin release. Even at normal K+ concentration, BPDZ-44 (50 mu M), which suppressed glucose-stimulated insulin release, only caused a partial inhibition of the insulinotropic action of A-4166 and failed to affect significantly insulin secretion in the presence of KAD-1229, repaglinide or S3075. These findings argue against the view that meglitinide analogues could affect cytosolic Ca2+ activity independently of the closing of ATP-sensitive K+ channels. The present results also indicate that, with the possible exception of A-4166 which in the least potent secretagogue in this series, meglitinide analogues are able, like hypoglycemic sulphonylureas, to fully protect ATP-sensitive K+ channels against their activation by BPDZ-44.
Malaisse
W J
WJ
Laboratory of Experimental Medicine, Brussels Free University, Belgium.
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D003510:Cyclohexanes / Q000494:pharmacology; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects*; D054833:Isoindoles; D000077715:Nateglinide; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D051381:Rats
D001549:Benzamides; D002219:Carbamates; D003510:Cyclohexanes; D007004:Hypoglycemic Agents; D007211:Indoles; D007328:Insulin; D054833:Isoindoles; D010880:Piperidines; C095585:S 3075; D000077715:Nateglinide; D010649:Phenylalanine; C072379:repaglinide; C087255:mitiglinide; D011188:Potassium