title: Effects of the beta-carbolines, harmane and pinoline, on insulin secretion from isolated human islets of Langerhans.
abstract: It is well known that certain imidazoline compounds can stimulate insulin secretion and this has been attributed to the activation of imidazoline I(3) binding sites in the pancreatic beta-cell. Recently, it has been proposed that beta-carbolines may be endogenous ligands having activity at imidazoline sites and we have, therefore, studied the effects of beta-carbolines on insulin secretion. The beta-carbolines harmane, norharmane and pinoline increased insulin secretion two- to threefold from isolated human islets of Langerhans. The effects of harmane and pinoline were dose-dependent (EC(50): 5 and 25 microM, respectively) and these agents also blocked the inhibitory effects of the potassium channel agonist, diazoxide, on glucose-induced insulin release. Stimulation of insulin secretion by harmane was glucose-dependent but, unlike the imidazoline I(3) receptor agonist efaroxan, it increased the rate of insulin release beyond that elicited by 20 mM glucose (20 mM glucose alone: 253+/-34% vs. basal; 20 mM glucose plus 100 microM harmane: 327+/-15%; P<0.01). Stimulation of insulin secretion by harmane was attenuated by the imidazoline I(3) receptor antagonist KU14R (2 (2-ethyl 2,3-dihydro-2-benzofuranyl)-2-imidazole) and was reduced when islets were treated with efaroxan for 18 h, prior to the addition of harmane. The results reveal that beta-carbolines can potentiate the rate of insulin secretion from human islets and suggest that these agents may be useful prototypes for the development of novel insulin secretagogues.
authors.affiliation: Cellular Pharmacology Group, School of Life Sciences, Keele University, Staffs ST5 5BG, UK.
authors.forename: E Jane
authors.initials: EJ
authors.lastname: Cooper
authors.forename: Alan L
authors.initials: AL
authors.lastname: Hudson
authors.forename: Christine A
authors.initials: CA
authors.lastname: Parker
authors.forename: Noel G
authors.initials: NG
authors.lastname: Morgan
mesh_terms: D000704:Analysis of Variance; D002243:Carbolines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology; D006247:Harmine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D002243:Carbolines; D007328:Insulin; C002272:6-methoxytryptoline; D006247:Harmine; C005010:harman; D005947:Glucose