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The Novel Imidazoline Compound BL11282 Potentiates Glucose-Induced Insulin Secretion in Pancreatic ß-Cells in the Absence of Modulation of K_ATP Channel Activity

¹ Rolf Luft Center for Diabetes Research, the Endocrine and Diabetes Unit, Department of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
² Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia
³ Department of Pharmacology, Lilly Research Laboratories, Lilly Forschung GmbH, Hamburg, Germany

The insulinotropic activity of the novel imidazoline compound BL11282 was investigated. Intravenous administration of BL11282 (0.3 mg · kg^–1 · 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 µmol/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.

Abbreviations: [Ca²⁺]_i, cytosolic free Ca²⁺ concentration; K_ATP, ATP-dependent K⁺ channel; KRBB, Krebs-Ringer bicarbonate buffer

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