As shown previously clonidine reduces glucose-stimulated insulin release and this effect is mediated by inhibitory postsynaptic alpha 2-adrenoceptors. The present experiments demonstrate that clonidine has the additional property to also stimulate insulin release. This became evident when the alpha 2-adrenoceptors of isolated islets were blocked by benextramine, and thus protected from being stimulated by clonidine. In the presence of benextramine, clonidine no longer reduced, but on the contrary enhanced, the release of insulin in response to glucose. In control experiments benextramine by itself failed to affect insulin release from isolated islets. These results show that the imidazoline derivative clonidine shares the property of other imidazoline compounds to enhance the insulin response to glucose. All of these agents may stimulate insulin by binding to "imidazoline-preferring" sites, that clearly differ from alpha-adrenoceptors.