Effects of α₂-adrenergic agonism, imidazolines, and G-protein on insulin secretion in β cells

It is well known that α₂-adrenergic agonism inhibits insulin secretion and stimulates glucagon secretion in both animal and human studies. Recently, α₂-adrenergic blockers (DG-5128, MK-912, and SL 84.0418) have been studied as antihyperglycemic agents in human subjects. To clarify the action mechanism(s) of these agents, we investigated the effects of α₂ agonists and antagonists (10^-10 to 10^-4 mol/L) and pretreatment by pertussis toxin (PT) on glucose-stimulated insulin secretion using the hamster insulinoma cell line HIT-T15. The imidazoline-derivative α₂-adrenoceptor agonists clonidine and oxymetazoline at concentrations as low as 10^-8 mol/L significantly inhibited glucose-stimulated insulin secretion by 63% and 65%, respectively (P < .01 for both). These inhibitory effects were abolished by 20-hour preincubation of these cells with PTX 100 ng/mL. The imidazoline- derivative α₂-adrenoceptor antagonist DG-5128 at a concentration of 10^-4 mol/L doubled insulin secretion with or without pretreatment by PTX (P < .01 for both). Furthermore, both clonidine and oxymetazoline at a high concentration of 10^-4 mol/L stimulated insulin secretion with pretreatment of the cells by PTX (P < .05 for both). These results indicate that glucose- stimulated insulin secretion is inhibited by α₂-adrenoceptor agonists through PTX-sensitive G-protein in HIT- T15 cells. It is also suggested that imidazoline compounds at high concentrations directly stimulate insulin secretion.