Imidazoline compounds stimulate insulin release by inhibition of K-ATP channels and interaction with the exocytotic machinery

A novel imidazoline compound, RX871024, was used to investigate the mechanisms by which imidazoline derivatives promote insulin secretion in rat pancreatic beta-cells and HIT T15 cells, RX871024 stimulated insulin release from rat pancreatic beta-cells and HIT T15 cells in a glucose-dependent way, This effect was not related to alpha(2)-adrenergic, I-1-, and I-2-imidazoline receptors. RX871024 promoted insulin release by at least two modes of action, One included an increase in cytoplasmic free Ca2+ concentration ([Ca2+](i)), subsequent to blocking of ATP-dependent K+ channels, membrane depolarization, and activation of voltage-dependent Ca2+ channels. The other, a more distal effect of imidazoline, affected the exocytotic machinery and was unrelated to changes in membrane potential and [Ca2+](i). The mechanism of RX871024-induced insulin release was dependent on protein kinases A and C. The sensitizing effect of a low dose of RX871024 on glucose-induced insulin secretion suggests that imidazoline compounds of this kind may constitute the basis for development of a new class of oral hypoglycemic agents.