Characterization of a K-ATP channel-independent pathway involved in potentiation of insulin secretion by efaroxan

Efaroxan, like several other imidazoline reagents, elicits a glucose-depend ent increase in insulin secretion from pancreatic beta -cells. This respons e has been attributed to efaroxan-mediated blockade of K-ATP channels, with the subsequent gating of voltage-sensitive calcium channels. However, incr easing evidence suggests that, at best, this mechanism can account for only part of the secretory response to the imidazoline. In support of this, we now show that efaroxan can induce functional changes in the secretory pathw ay of pancreatic beta -cells that are independent of K-ATP channel blockade . In particular, efaroxan was found to promote a sustained sensitization of glucose-induced insulin release that persisted after removal of the drug a nd to potentiate Ca2+-induced insulin secretion from electropermeabilized i slets. To investigate the mechanisms involved, me studied the effects of th e efaroxan antagonist KU14R. This agent is known to selectively inhibit ins ulin secretion induced by efaroxan, without altering the secretory response to glucose or KCl. Surprisingly, however, KU14R markedly impaired the pote ntiation of insulin secretion mediated by agents that raise cAMP, including the adenylate cyclase activator, forskolin, and the phosphodiesterase inhi bitor isobutylmethyl xanthine (IBMX). These effects were not accompanied by any reduction in cAMP levels, suggesting an antagonistic action of KU14R a t a more distal point in the pathway of potentiation. In accord with our pr evious work, islets that were exposed to efaroxan for 24 h became selective ly desensitized to this agent, but they still responded normally to glucose . Unexpectedly however the ability of either forskolin or IBMX to potentiat e glucose-induced insulin secretion was severely impaired in these islets. By contrast, the elevation of cAMP was unaffected by culture of islets with efaroxan. Taken together, the data suggest that, in addition to effects on the K-ATP channel, imidazolines also interact with a more distal component that is crucial to the potentiation of insulin secretion. This component i s not required for Ca2+-dependent secretion per se but is essential to the mechanism by which cAMP potentiates insulin release. Overall, the results i ndicate that the actions of efaroxan at this distal site may be more import ant for control of insulin secretion than its effects on the K-ATP channel.