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 Ca(2+) or in the presence of the Ca(2+)-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 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.
Straub
Susanne G
SG
Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA.
Mulvaney-Musa
Jennifer
J
Yajima
Hiroki
H
Weiland
Gregory A
GA
Sharp
Geoffrey W G
GW
D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D051381:Rats; D013649:Taste
D007328:Insulin; D000644:Quaternary Ammonium Compounds; C043414:denatonium