title: The novel imidazoline compound BL11282 potentiates glucose-induced insulin secretion in pancreatic beta-cells in the absence of modulation of K(ATP) channel activity.
abstract: The insulinotropic activity of the novel imidazoline compound BL11282 was investigated. Intravenous administration of BL11282 (0.3 mg x kg(-1) x min(-1)) to anesthetized rats did not change blood glucose and insulin levels under basal conditions, but produced a higher increase in blood insulin levels and a faster glucose removal from the blood after glucose infusion. Similarly, in isolated Wistar rat pancreatic islets, 0.1-100 micromol/l BL11282 potently stimulated glucose-induced insulin secretion but did not modulate basal insulin secretion. Unlike previously described imidazolines, BL11282 did not block ATP-dependent K+ channels. Furthermore, the compound stimulated insulin secretion in islets depolarized with high concentrations of KCl or permeabilized with electric shock. Insulinotropic activity of BL11282 was dependent on activity of protein kinases A and C. In pancreatic islets from spontaneously diabetic GK rats, the imidazoline compound restored the impaired insulin response to glucose. In conclusion, the imidazoline BL11282 constitutes a new class of insulinotropic compounds that exerts an exclusive glucose-dependent insulinotropic activity in pancreatic islets by stimulating insulin exocytosis.
authors: Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: A M
authors: AM
authors: Efanov
authors: S V
authors: SV
authors: Zaitsev
authors: H J
authors: HJ
authors: Mest
authors: A
authors: A
authors: Raap
authors: I B
authors: IB
authors: Appelskog
authors: O
authors: O
authors: Larsson
authors: P O
authors: PO
authors: Berggren
authors: S
authors: S
authors: Efendic
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D004357:Drug Synergism; D004558:Electric Stimulation; D005947:Glucose / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D015221:Potassium Channels / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
chemical_list: C423844:BL 11282; D007093:Imidazoles; D007328:Insulin; D015221:Potassium Channels; D011189:Potassium Chloride; D000255:Adenosine Triphosphate; D005947:Glucose