Although several models of experimental diabetes mellitus are currently available, none of them appears to be optimally suited to study the possible deleterious effect of sustained hyperglycemia upon biochemical and functional variables in pancreatic islet cells in the absence of chronic stimulation of secretory activity. In the present study, oral diazoxide administration (0.33 g/Kg body wt. thrice per day for three days) to rats was used to cause both hypoinsulinemia and hyperglycemia (greater than or equal to 10.0 mM), the latter persisting, albeit at a somewhat lower level, for at least 1-2 days after cessation of diazoxide treatment. Ten hours after the last administration of diazoxide, the secretory response of isolated islets to D-glucose over 90 min incubation was not impaired. It is proposed that such a model may help to dissociate the influence of hyperglycemia itself upon islet cell behaviour from the consequences of sustained hypersecretion of insulin.