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 acute 20-min incubations, 50-400 microM 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 microM tolbutamide (18 hr) caused a marked (67%) decrease in subsequent insulin-secretory responsiveness to acute challenge with 200 microM tolbutamide, though notably, tolbutamide culture exerted no influence on 200 microM efaroxan-induced insulin secretion. Duration of exposure (3-18 hr) to 100 microM 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 microM 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.
School of Biomedical Sciences, University of Ulster, BT52 1SA, Coleraine, Northern Ireland, UK. nh.mcclenaghan@ulst.ac.uk
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McClenaghan
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Ball
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Flatt
D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D002460:Cell Line; D004347:Drug Interactions; D005947:Glucose / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D013997:Time Factors; D014044:Tolbutamide / Q000494:pharmacology*
D001572:Benzofurans; D007004:Hypoglycemic Agents; D007093:Imidazoles; D007328:Insulin; D013453:Sulfonylurea Compounds; D014044:Tolbutamide; C062597:efaroxan; D005947:Glucose