Clonidine-displacing substance and its putative role in control of insulin secretion: a minireview.

1. Imidazoline-binding sites, or I-sites, are a class of recently defined nonadrenoceptor recognition sites whose most potent ligands are imidazolines and related compounds. 2. The pancreatic islet beta-cell I-site, which mediates imidazoline-induced stimulation of insulin release, appears to be the first site to be pharmacologically defined with selective agonists and antagonists. 3. The natural ligand for imidazoline recognition sites is still unknown. The strongest candidate is clonidine-displacing substance (CDS), originally identified in extracts of rat and bovine brain. However, the bioactive molecule has not been identified definitively. Agmatine, a decarboxylated derivative of arginine, also binds to both I-sites and alpha2-adrenoceptors (Li et al., 1994), and is, by definition, a CDS molecule. 4. In the endocrine pancreas, agmatine is a weak insulin secretagogue, which induces a slowly developing secretory response. However, this profile does not correlate with interaction at the islet I-site, and thus agmatine is unlikely to be an endogenous secretagogue acting functionally at the islet I-site. 5. Crude preparations of CDS from rat brain can potentiate glucose-induced insulin release and reverse the effects of diazoxide in rat and human islets of Langerhans. These two effects are also subject to blockade by the imidazoline antagonists RX801080 and KU14R. Furthermore, islets that were desensitized to the effects of the imidazoline secretagogue efaroxan (after 18-hr culture with imidazoline) were refractory to the actions of CDS. 6. Overall, CDS displays many characteristics expected of an endogenous regulator of insulin secretion acting through the islet beta-cell imidazoline site. This evidence strengthens the hypothesis that the islet beta-cell imidazoline site mediating control of insulin release in the endocrine pancreas is a biologically relevant receptor. Furthermore, a physiological role of CDS in the endocrine pancreas cannot be excluded.