Actions of antipsychotic drugs on pancreatic β-cell function:: contrasting effects of clozapine and haloperidol

The use of antipsychotic drugs is known to be associated with a number of adverse metabolic side effects, including diabetes mellitus. These side effects could be, at least in part, the result of impaired islet cell function, although the underlying mechanisms are unknown. We have studied the effects of the atypical antipsychotic clozapine and of the conventional drug haloperidot on electrical and secretory activity in rat pancreatic P-celts. At a tow glucose concentration (4mM), clozapine (5 mu M) had little or no effect on membrane potential. However, at a stimulatory glucose concentration (16 mM), clozapine was found to hyperpolarize the cell membrane potential, resulting in a complete inhibition of electrical activity. In contrast, hatoperidol (5 mu M) was found to cause a marked depolarization of the membrane potential in the presence of both tow and high concentrations of glucose. Clozapine and haloperidol were found, respectively, to increase and decrease beta-cett input conductance, an index of K+ permeability. Single channel recordings indicated that changes in K-ATP channel activity contributed towards these effects. Neither clozapine nor hatoperidol affected basal insulin release, although clozapine inhibited glucose-induced insulin release. It is concluded that clozapine and haloperidol exert contrasting actions on electrical activity in rat pancreatic beta-cells as a result of opposing effects on K+ permeability. These findings may relate to the increased incidence of diabetes associated with clozapine treatment.