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

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 ß-cells and rat pancreatic islets. Stimulation of release began promptly after exposure of the ß-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 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 ß-cell. The results indicate that denatonium stimulates insulin secretion by decreasing KATP channel activity, depolarizing the ß-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.

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