Effects of a peripheral-type benzodiazepine on glucose-induced insulin secretion.

Benzodiazepines, besides interacting with central-type receptors which mediate their well-known pharmacological actions, bind to peripheral-type receptors that are distributed in a variety of peripheral tissues including numerous endocrine organs. The present work was designed to investigate the effects of a selective peripheral-type benzodiazepine, 4'-chlordiazepam (Ro 5-4864), on glucose-induced insulin secretion in vitro. In the rat isolated pancreas perfused with a Krebs-bicarbonate buffer containing 8.3 mM glucose, the drug (10(-6) and 10(-5) M) induced a progressive and significant decrease in insulin release. Concomitantly, it induced a vasodilator response of the pancreatic vascular bed. In rat isolated islets incubated for 1 h in the presence of 15 mM glucose, 4'-chlordiazepam (10(-5) and 10(-4) M) induced a significant and dose-dependent inhibition of insulin release. In contrast, the selective central-type benzodiazepine, clonazepam (10(-6) - 10(-4) M), did not significantly modify glucose-induced insulin secretion. In addition, experiments were performed to test the effect of 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamid e (PK 11195), a peripheral non-benzodiazepine ligand proposed as a putative antagonist. This substance did not counteract the inhibitory effect of 4'-chlordiazepam but itself (10(-6) and 10(-5) M) elicited a potent inhibitory effect on insulin secretion. These results show that drugs such as 4'-chlordiazepam and PK 11195 which have a high affinity for peripheral-type benzodiazepine receptors, in contrast to a central-type benzodiazepine agonist, inhibit glucose-induced insulin secretion in vitro.