EFFECTS OF ALPHA(2)-ADRENERGIC AGONISM, IMIDAZOLINES, AND G-PROTEIN ON INSULIN-SECRETION IN BETA-CELLS

It is well known that alpha(2)-adrenergic agonism inhibits insulin sec retion and stimulates glucagon secretion in both animal and human stud ies. Recently, alpha(2)-adrenergic blockers (DG-5128, MIK-912, and St. 84.0418) have been studied as antihyperglycemic agents in human subje cts. To clarify the action mechanism(s) of these agents, we investigat ed the effects of alpha(2) agonists and antagonists (10(-10) to 10(-4) mol/L) and pretreatment by pertussis toxin (PTX) on glucose-stimulate d insulin secretion using the hamster insulinoma cell line HIT-T15. Th e imidazoline-derivative alpha(2)-adrenoceptor agonists clonidine and oxymetazoline at concentrations as low as 10(-8) mol/L significantly i nhibited glucose-stimulated insulin secretion by 63% and 65%, respecti vely (P < .01 for both). These inhibitory effects were abolished by 20 -hour preincubation of these cells with PTX 100 ng/mL, The imidazoline -derivative alpha(2)-adrenoceptor antagonist DG-5128 at a concentratio n of 10(-4) mol/L doubled insulin secretion with or without pretreatme nt by PTX (P < .01 for both). Furthermore, both clonidine and oxymetaz oline at a high concentration of 10(-4) mol/L stimulated insulin secre tion with pretreatment of the cells by PIX (P < .05 for both), These r esults indicate that glucose-stimulated insulin secretion is inhibited by alpha(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. Copyright (C) 19 97 by W.B. Saunders Company.