Mechanism of the Stimulation of Insulin Release in Vitro by HB 699, a Benzoic Acid Derivative Similar to the Non-Sulphonylurea Moiety of Glibenclamide

Diabetologia. 1985 Sep;28(9):697-703. doi: 10.1007/BF00291979.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / antagonists & inhibitors
  • Benzamides / pharmacology*
  • Calcium / metabolism
  • Diazoxide / pharmacology
  • Female
  • Glucose / pharmacology
  • Glyburide / pharmacology
  • Hypoglycemic Agents / pharmacology*
  • In Vitro Techniques
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism*
  • Kinetics
  • Mice
  • Mice, Inbred Strains
  • Rubidium / metabolism

Substances

  • Benzamides
  • Hypoglycemic Agents
  • Insulin
  • meglitinide
  • Glucose
  • Rubidium
  • Diazoxide
  • Glyburide
  • Calcium