Effects of α 2-adrenergic agonism, imidazolines, and G-protein on insulin secretion in β cells

Abstract

It is well known that α 2-adrenergic agonism inhibits insulin secretion and stimulates glucagon secretion in both animal and human studies. Recently, α 2-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 α 2 agonists and antagonists (10 −10 to 10 −4 mol/L) and pretreatment by pertussis toxin (PTX) on glucose-stimulated insulin secretion using the hamster insulinoma cell line HiT-T15. The imidazoline-derivative α 2-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 α 2-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 α 2-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.