Stimulation of Insulin Secretion by Denatonium, One of the Most Bitter-Tasting Substances Known

Stimulation of Insulin Secretion by Denatonium, One of the Most Bitter-Tasting Substances Known Susanne G. Straub , Jennifer Mulvaney-Musa , Hiroki Yajima , Gregory A. Weiland and Geoffrey W.G. Sharp From the Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York Abstract Denatonium, one of the most bitter-tasting substances known, stimulated insulin secretion in clonal HIT-T15 β-cells and rat pancreatic islets. Stimulation of release began promptly after exposure of the β-cells to denatonium, reached peak rates after 4–5 min, and then declined to near basal values after 20–30 min. In islets, no effect was observed at 2.8 mmol/;l glucose, whereas a marked stimulation was observed at 8.3 mmol/;l glucose. No stimulation occurred in the absence of extracellular Ca 2+ or in the presence of the Ca 2+ -channel blocker nitrendipine. Stimulated release was inhibited by α 2 -adrenergic agonists. Denatonium had no direct effect on voltage-gated calcium channels or on cyclic AMP levels. There was no evidence for the activation of gustducin or transducin in the β-cell. The results indicate that denatonium stimulates insulin secretion by decreasing KATP channel activity, depolarizing the β-cell, and increasing Ca 2+ influx. Denatonium did not displace glybenclamide from its binding sites on the sulfonylurea receptor (SUR). Strikingly, it increased glybenclamide binding by decreasing the K d . It is concluded that denatonium, which interacts with K + channels in taste cells, most likely binds to and blocks Kir6.2. A consequence of this is a conformational change in SUR to increase the SUR/;glybenclamide binding affinity. Footnotes Address correspondence and reprint requests to Dr. Geoffrey W.G. Sharp, Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853-6401. E-mail: gws2{at}cornell.edu . Received for publication 8 April 2002 and accepted in revised form 17 October 2002. PMSF, phenylmethylsulfonyl fluoride; SUR, sulfonylurea receptor. DIABETES