Abstract

Functional effects of prolonged exposure to the sulfonylurea, tolbutamide, were examined in the clonal electrofusion-derived BRIN-BD11 cell Line. In acute 20-min incubations, 50-400 muM tolbutamide stimulated a dose-dependent increase (P < 0.01) in insulin release at both non-stimulatory (1.1 mM) and stimulatory (8.4 mM) glucose. Culture with 100 muM tolbutamide (18 hr) caused a marked (67%) decrease in subsequent insulin-secretory responsiveness to acute challenge with 200 muM tolbutamide, though notably, tolbutamide culture exerted no influence on 200 muM efaroxan-induced insulin secretion. Duration of exposure (3-18 hr) to 100 muM tolbutamide in culture also time-dependently influenced subsequent responsiveness to acute tolbutamide challenge, with progressive 47-58% decreases from 6-18 hr (P < 0.001). Similarly, 6- to 18-hr culture with 100 muM efaroxan specifically desensitized efaroxan-induced insulin release. Tolbutamide- and efaroxan-induced desensitization exhibited a time-dependent reversibility, with a sustained return to full insulin-secretory responsiveness by 12 hr. Notably, 18-hr culture with tolbutamide or efaroxan did not significantly affect insulinotropic responses to 16.7 mM glucose, 10 mM 2-ketoisocaproic acid, 10 mM alanine, 10 mM arginine, or 30 mM KCl. Diverse inhibitory actions of tolbutamide or efaroxan culture on late events in stimulus-secretion coupling reveal that drug desensitization is both a specific and important phenomenon. As such, the model system described could prove an important tool in determining the complex modes of action of established and novel clinically useful insulinotropic compounds. (C) 2001 Elsevier Science Inc. All rights reserved.