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 β-cells and HIT T15 cells. RX871024 stimulated insulin release from rat pancreatic β-cells and HIT T15 cells in a glucose-dependent way. This effect was not related to α2-adrenergic, I₁-, and I₂-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.