SIGMA-RECEPTOR LIGANDS AND IMIDAZOLINE SECRETAGOGUES MEDIATE THEIR INSULIN SECRETORY EFFECTS BY ACTIVATING DISTINCT RECEPTOR SYSTEMS IN ISOLATED ISLETS

The effects of two potent sigma receptor agonists (+)-3-PPP ((R)-3-(3- hydroxyphenyl)-N-(1-propyl)piperidine) and DTG (N,N'-di-(o-tolyl)guani dine) on the insulin secretory responses in rat islets of Langerhans w ere investigated. Both sigma receptor ligands were able to potentiate the insulin secretory response of islets incubated at 6 mM glucose, in a dose-dependent manner and were also able to reverse the effects of diazoxide on insulin release. When islets were treated with efaroxan, a well-characterised imidazoline insulin secretagogue, and either (+)- 3-PPP or DTG together, there was an unexpected and profound absence of stimulation of insulin release as compared to when islets were incuba ted with each compound alone. Experiments performed with islets where there was desensitization of DTG/sigma receptor or efaroxan/imidazolin e binding site mediated responses suggest that at least two distinct r eceptor systems appear to be involved. The complex interactions of the se two classes of drug require further investigation. (C) 1998 Elsevie r Science B.V. All rights reserved.