title: Effects of alpha 2-adrenergic agonism, imidazolines, and G-protein on insulin secretion in beta cells.
abstract: It is well known that alpha 2-adrenergic agonism inhibits insulin secretion and stimulates glucagon secretion in both animal and human studies. Recently, alpha 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 alpha 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 alpha 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 alpha 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 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.
authors.affiliation: Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Hirose
authors.forename: Y
authors.initials: Y
authors.lastname: Seto
authors.forename: H
authors.initials: H
authors.lastname: Maruyama
authors.forename: K
authors.initials: K
authors.lastname: Dan
authors.forename: K
authors.initials: K
authors.lastname: Nakamura
authors.forename: T
authors.initials: T
authors.lastname: Saruta
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D006224:Cricetinae; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007340:Insulinoma; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D015394:Molecular Structure; D010109:Oxymetazoline / Q000494:pharmacology; D010190:Pancreatic Neoplasms; D037342:Pertussis Toxin; D010646:Phentolamine / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011807:Quinolizines / Q000494:pharmacology; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D014407:Tumor Cells, Cultured; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D007093:Imidazoles; D007211:Indoles; D007328:Insulin; D011758:Pyrroles; D011807:Quinolizines; D018341:Receptors, Adrenergic, alpha-2; D010566:Virulence Factors, Bordetella; C054290:L 657743; C074936:SL 84.0418; C032368:midaglizole; D010109:Oxymetazoline; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D005947:Glucose; D003000:Clonidine; D010646:Phentolamine