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 me chanisms by which imidazoline derivatives promote insulin secretion in rat pancreatic beta-cells and HIT T15 cells, RX871024 stimulated insu lin release from rat pancreatic beta-cells and HIT T15 cells in a gluc ose-dependent way, This effect was not related to alpha(2)-adrenergic, I-1-, and I-2-imidazoline receptors. RX871024 promoted insulin releas e by at least two modes of action, One included an increase in cytopla smic free Ca2+ concentration ([Ca2+](i)), subsequent to blocking of AT P-dependent K+ channels, membrane depolarization, and activation of vo ltage-dependent Ca2+ channels. The other, a more distal effect of imid azoline, affected the exocytotic machinery and was unrelated to change s in membrane potential and [Ca2+](i). The mechanism of RX871024-induc ed insulin release was dependent on protein kinases A and C. The sensi tizing effect of a low dose of RX871024 on glucose-induced insulin sec retion suggests that imidazoline compounds of this kind may constitute the basis for development of a new class of oral hypoglycemic agents.