Stimulation Of Insulin Secretion By Denatonium, One Of The Most Bitter-Tasting Substances Known

Denatonium, one of the most bitter-tasting substances known, stimulated insulin secretion in clonal HIT-T15 beta-cells and rat pancreatic islets. Stimulation of release began promptly after exposure of the beta-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 alpha(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 beta-cell. The results indicate that denatonium stimulates insulin secretion by decreasing KATP channel activity, depolarizing the beta-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 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.