Mechanism of the stimulation of insulin release in vitro by HB 699, a benzoic acid derivative similar to the non-sulphonylurea moiety of glibenclamide.
HB 699 is a benzoic acid derivative similar to the non-sulphonylurea moiety of glibenclamide. The mechanisms whereby it affects B-cell function have been studied in vitro with mouse islets. In the presence of 3 mmol/l glucose, HB 699 decreased 86Rb+ efflux and accelerated 45Ca2+ efflux from islet cells, depolarized the B-cell membrane and induced an electrical activity similar to that triggered by stimulatory concentrations of glucose, and increased insulin release. The changes in 45Ca2+ efflux and insulin release, but not the inhibition of 86Rb+ efflux, were abolished in the absence of Ca2+. In the presence of 10 mmol/l glucose, HB 699 increased 86Rb+ and 45Ca2+ efflux from the islets, caused a persistent depolarization of the B-cell membrane with continuous electrical activity and markedly potentiated insulin release. All these changes were suppressed by omission of extracellular Ca2+. In the presence of 15 mmol/l glucose, diazoxide increased 86Rb+ efflux, hyperpolarized the B-cell membrane, suppressed electrical activity and inhibited insulin release. HB 699 reversed these effects of diazoxide. It is suggested that HB 699 decreases K+ permeability of the B-cell membrane, thereby causing a depolarization which leads to activation of voltage-dependent Ca channels and Ca2+ influx, and eventually increases insulin release. A sulphonylurea group is thus not a prerequisite to trigger the sequence of events that is also thought to underlie the releasing effects of tolbutamide and glibenclamide.
D000818:Animals; D001549:Benzamides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D005260:Female; D005947:Glucose / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D008815:Mice, Inbred Strains; D012413:Rubidium / Q000378:metabolism
D001549:Benzamides; D007004:Hypoglycemic Agents; D007328:Insulin; C030516:meglitinide; D005947:Glucose; D012413:Rubidium; D003981:Diazoxide; D005905:Glyburide; D002118:Calcium