DISSOCIATION BETWEEN THE POTENCY AND REVERSIBILITY OF THE INSULINOTROPIC ACTION OF 2 MEGLITINIDE ANALOGS

The non-sulphonylurea hypoglycaemic agent repaglinide is about one ord er of magnitude less potent, in terms of insulinotropic efficiency, th an S3075, another meglitinide analogue. In the present study, the effe cts of these two drugs upon Rb-86 outflow, Ca-45 efflux and insulin re lease from prelabelled rat pancreatic islets were investigated in a pe rifusion system. At a concentration of 10 mu M, which is sufficient to evoke a maximal secretory response in incubated islets, both agents i nhibited Rb-86 efflux from islets perifused in the absence of D-glucos e, and stimulated both Ca-45 efflux and insulin release from islets pe rifused in the presence of 6 mM D-glucose. The stimulation of Ca-45 ef flux from prelabelled islets was suppressed in the absence of extracel lular Ca2+. The cationic and secretory response to repaglinide differe d, however, from that evoked by S3075, in persisting for at least 20 m in after removal of the drug from the perifusion medium, whilst the ch anges in Rb-86 outflow, Ca-45 efflux and insulin release caused by S30 75 were rapidly reversible. These findings indicate that there is no p arallel between the insulinotropic efficiency of distinct meglitinide analogues, and the reversibility of their functional effects. Since a comparable dissociation was recently documented in the case of hypogly caemic sulphonylureas, the present observations reinforce the view tha t distinct molecular determinants may rule the relative insulinotropic potency of sulphonylureas and structurally related meglitinide analog ues, on one hand, and the reversibility of their biological action, on the other hand. (C) 1996 The Italian Pharmacological Society.