Specific desensitization of sulfonylurea- but not imidazoline-induced insulin release after prolonged tolbutamide exposure

Functional effects of prolonged exposure to the sulfonylurea, tolbutamide, were examined in the clonal electrofusion-derived BRIN-BD11 cell Line. In a cute 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) an d stimulatory (8.4 mM) glucose. Culture with 100 <mu>M tolbutamide (18 hr) caused a marked (67%) decrease in subsequent insulin-secretory responsivene ss 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 tim e-dependently influenced subsequent responsiveness to acute tolbutamide cha llenge, with progressive 47-58% decreases from 6-18 hr (P < 0.001). Similar ly, 6- to 18-hr culture with 100 <mu>M efaroxan specifically desensitized e faroxan-induced insulin release. Tolbutamide- and efaroxan-induced desensit ization exhibited a time-dependent reversibility, with a sustained return t o full insulin-secretory responsiveness by 12 hr. Notably, 18-hr culture wi th tolbutamide or efaroxan did not significantly affect insulinotropic resp onses 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 efaro xan culture on late events in stimulus-secretion coupling reveal that drug desensitization is both a specific and important phenomenon. As such, the m odel system described could prove an important tool in determining the comp lex modes of action of established and novel clinically useful insulinotrop ic compounds. (C) 2001 Elsevier Science Inc. All rights reserved.