title: Dissection of mechanisms that account for imidazoline-induced lowering of blood glucose in mice.
abstract: Multiple mechanisms have been suggested to be responsible for the insulinotropic and blood glucose lowering effects of imidazoline compounds. This study was to unravel which mechanism predominantly accounts for glucose lowering by the prototypical imidazolines idazoxan and phentolamine. To this end, an α2-adrenoceptor agonist (UK14,304) and a KATP channel opener (diazoxide) were used to inhibit insulin release from isolated perifused mouse islets and to induce hyperglycaemia in conscious mice. Potentials of idazoxan and phentolamine to counteract these effects were examined in a comparative manner. In perifused islets, idazoxan increased insulin release only in the presence of the α2-agonist, whereas phentolamine strongly counteracted both inhibitors of insulin release. In vivo, a lower dose of idazoxan was necessary to ameliorate hyperglycaemia induced by the α2-agonist than by the KATP channel opener, indicating α2A-antagonism as the predominant mechanism of action (decrease in incremental area under the glucose curve induced by 0.1mg/kg idazoxan: under diazoxide, -3±7%, vs. under UK14,304, -34±9%, P<0.02). In contrast, identical doses of phentolamine were required to counteract hyperglycaemia induced by the two inhibitors of insulin release, implicating involvement of another mechanism beside α2A-antagonism (2mg/kg phentolamine: diazoxide, -11±8%, vs. UK14,304, -15±9%, ns; 4mg/kg phentolamine: diazoxide, -48±6%, vs. UK14,304, -48±8%, ns). The results show that imidazolines can lower blood glucose via more than one mechanism of action, with the relative contributions of the mechanisms varying considerably between individual compounds. Dissection of the involved mechanisms could help to develop imidazoline drugs for the treatment of type 2 diabetes.
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. Electronic address: karin.stadlbauer@gmx.at.
authors.forename: Karin
authors.initials: K
authors.lastname: Stadlbauer
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. Electronic address: Zsuzsanna.Lehner@gmx.at.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Lehner
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. Electronic address: n0701994@students.meduniwien.ac.at.
authors.forename: Natasa
authors.initials: N
authors.lastname: Stamenkovic
authors.affiliation: Institute of Pharmacology and Toxicology, University of Braunschweig, Mendelssohnstraße 1, 38106 Braunschweig, Germany. Electronic address: i.rustenbeck@tu-bs.de.
authors.forename: Ingo
authors.initials: I
authors.lastname: Rustenbeck
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. Electronic address: lidia.surman@yahoo.de.
authors.forename: Lidia
authors.initials: L
authors.lastname: Surman
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. Electronic address: anton.luger@meduniwien.ac.at.
authors.forename: Anton
authors.initials: A
authors.lastname: Luger
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. Electronic address: clemens.fuernsinn@meduniwien.ac.at.
authors.forename: Clemens
authors.initials: C
authors.lastname: Fürnsinn
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism*; D048288:Imidazolines / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D001786:Blood Glucose; D048288:Imidazolines; D007328:Insulin
keywords: Idazoxan; Imidazoline; K(ATP) channel; Phentolamine; UK14 304 (CID 2435); diazoxide (CID 58 3019); idazoxan (CID 54459); phentolamine (CID 5775); α(2)-adrenoceptor