Imidazoline binding sites in the endocrine pancreas: Can they fulfil theirpotential as targets for the development of new insulin secretagogues?

A variety of compounds containing an imidazoline ring have the ability to s timulate insulin secretion. Many of these also improve glycaemia in experim ental models of type 2 diabetes and in man, suggesting that this class may be useful in the development of new orally active anti-diabetic drugs. Howe ver, the mechanisms by which imidazolines promote insulin secretion have no t been clarified. The response does not appear to be due to the binding of ligands to either of the two major types of "imidazoline receptor" defined by pharmacological criteria (I-1 and I-2 sites) but may result from interac tion with a novel imidazoline binding site. One such site has been identifi ed in association with the ATP-sensitive potassium (K-ATP) channel in the b eta -cell and has been designated "I-3". Electrophysiological and biochemic al evidence suggest that the I-3 site may be intrinsic to the ion-conductin g pore component, Kir6.2, of the K-ATP channel, but the effects of imidazol ine ligands on insulin secretion can be dissociated from the regulation of Kir6.2. Indeed, there is increasing evidence that some imidazolines can con trol exocytosis directly, both in beta -cells and in pancreatic alpha -cell s. Thus, it is proposed that a further imidazoline binding site is primaril y responsible for control of hormone secretion. Evidence is reviewed which suggests that this site occupies a central position within an amplification pathway that also mediates the effects of cAMP in the beta -cell. Characte risation of this site should provide the stimulus for the design of new ins ulin secretagogues that are devoid of K-ATP channel-blocking properties.