Section Review: Oncologic, Endocrine and Metabolic Adrenoceptors and imidazoline binding sites in the endocrine pancreas as targets for anti-hyperglycaemic drugs

Abstract

The rate of insulin secretion from the endocrine pancreas is controlled principally by metabolic stimuli, although other agents, including hormones and neurotransmitters, are important modulators of insulin secretion. Among these, the catecholamines are particularly effective inhibitors of insulin secretion; a response that is mediated by activation of alpha-2-adrenoceptors present on islet B-cells. In view of the potent inhibitory effects of catecholamines on insulin secretion, the proposition has been advanced that increased sympathetic nervous activity (or enhanced islet responsiveness to catecholamines) might contribute to the impairment of insulin secretion observed in certain patients with non-insulin-dependent diabetes mellitus. If true, then it follows that circulating insulin levels should be increased upon administration of alpha-2-adrenoceptor antagonists to such patients. Evidence has accumulated which supports this concept, although this evidence is equivocal since the insulin secretagogue activity of alpha-antagonists does not always correlate well with their affinity for alpha-2-adrenoceptors. Many of the alpha-2-antagonists which can improve glycaemic control in vivo and stimulate insulin secretion in vitro, induce closure of islet cell ATP-sensitive potassium channels in a manner that is independent of alpha-2-adrenoceptor binding. This activity appears to correlate with the possession of an imidazoline ring (or a similar motif) within the structure. Thus, a new possibility has now emerged, that control of insulin secretion by alpha-2-antagonists may reflect binding to a novel imidazoline receptor site in islets (which controls membrane potassium permeability) rather than blockade of alpha-2-adrenoceptors.