CLOTRIMAZOLE AND EFAROXAN STIMULATE INSULIN-SECRETION BY DIFFERENT MECHANISMS IN RAT PANCREATIC-ISLETS

It is now well established that the imidazoline insulin secretagogue e faroxan mediates its effects by inducing closure of ATP-sensitive pota ssium channels in the pancreatic beta-cell, leading to membrane depola risation, Ca2+ influx and increased insulin secretion. However, a rece nt study has shown that efaroxan may also act as a blocker of a second class of potassium channel (the K-maxi channel) in red blood cells, r aising the possibility that its effects in islets could be mediated by interactions with both types of channel. Since the antimycotic imidaz ole compound clotrimazole is a highly potent blocker of K-maxi channel s, we have studied the effects of this drug on insulin secretion. Clot rimazole stimulated insulin secretion from rat islets of Langerhans in cubated in the presence of 6 mM glucose, in a dose-dependent manner. E xperiments performed at different glucose concentrations showed that t he actions of clotrimazole were most prominent at low glucose concentr ations whereas it did not enhance secretion beyond the rate induced by 20 mM glucose. The insulinotropic action of clotrimazole was temperat ure dependent but was independent of extracellular calcium. Clotrimazo le appeared to block ATP-sensitive potassium channels in islets since, like efaroxan and glibencamide, it was able to prevent the inhibitory effects of diazoxide on glucose-induced insulin secretion. However, n either the direct stimulatory effect of clotrimazole on insulin releas e nor the abilty of clotrimazole to reverse the inhibitory actions of diazoxide was sensitive to blockade by the imidazoline secretagogue an tagonist KU14R. Overall, the results suggest that clotrimazole exerts an insulinotropic effect in pancreatic beta-cells that is distinct fro m the actions of imidazoline secretagogues such as efaroxan. Clotrimaz ole can increase insulin secretion at sub-maximal glucose concentratio ns by an action which appears to be independent of membrane ion channe l events.