THE EFFECT OF THE PUTATIVE ENDOGENOUS IMIDAZOLINE RECEPTOR-LIGAND, CLONIDINE-DISPLACING SUBSTANCE, ON INSULIN-SECRETION FROM RAT AND HUMAN ISLETS OF LANGERHANS

1 The effects of a rat brain extract containing clonidine-displacing s ubstance (CDS), a putative endogenous imidazoline receptor ligand, on insulin release from rat and human isolated islets of Langerhans were investigated. 2 CDS was able to potentiate the insulin secretory respo nse of rat islets incubated at 6 mM glucose, in a dose-dependent manne r. The magnitude of this effect was similar to that in response to the well-characterized imidazoline secretagogue, efaroxan. 3 CDS, like ot her imidazoline secretagogues, was also able to reverse the inhibitory action of diazoxide on glucose-induced insulin release, in both rat a nd human islets. 4 These effects of CDS on secretion were reversed by the imidazoline secretagogue antagonists, RX801080 and the newly defin ed KU14R, providing the first evidence that imidazoline-mediated actio ns of CDS can be blocked by specific imidazoline antagonists. 5 The ef fects of CDS on insulin secretion were unaffected when the method of p reparation involved centri-filtration through a 3,000 Da cut-off membr ane or when the extract was treated with protease. These results confi rm that the active principle is of low molecular weight and is not a p eptide. 6 Overall, the data suggest that CDS behaves as a potent endog enous insulin secretagogue acting at the islet imidazoline receptor.