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
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 Ca2+ or in the presence of the Ca2+-channel blocker nitrendipine. Stimulated release was inhibited by α2-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 Ca2+ influx. Denatonium did not displace glybenclamide from its binding sites on the sulfonylurea receptor (SUR). Strikingly, it increased glybenclamide binding by decreasing the Kd. 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.
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:.
Received for publication 8 April 2002 and accepted in revised form 17 October 2002.
PMSF, phenylmethylsulfonyl fluoride; SUR, sulfonylurea receptor.