TY - JOUR T1 - A Novel Enhancer of Insulinotrophic Action by High Glucose (JTT-608) Stimulates Insulin Secretion from Pancreatic β-Cells via a New Cellular Mechanism JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 953 LP - 960 VL - 297 IS - 3 AU - Naoki Itabashi AU - Koji Okada AU - Shigeaki Muto AU - Nobuya Fujita AU - Takeshi Ohta AU - Jun-ichi Miyazaki AU - Yasushi Asano AU - Toshikazu Saito Y1 - 2001/06/01 UR - http://jpet.aspetjournals.org/content/297/3/953.abstract N2 - Insulin secretion from MIN6 cells (a pancreatic β-cell line) induced by high glucose (greater than 16.8 mM) was potentiated by a novel hypoglycemic agent [trans-4-(4-methylcyclohexyl)-4-oxobutyric acid (JTT-608)] (but not glibenclamide, a sulfonylurea). The extracellular Ca2+-free condition, a L-type Ca2+ channel blocker (nifedipine) and an ATP-sensitive K+ channel opener, diazoxide, completely inhibited increases in cytosolic free Ca2+ ([Ca2+]i) and insulin secretion evoked by JTT-608 in the presence of extracellular Ca2+. An electrophysiological study using single-barreled microelectrode techniques demonstrated that membrane potential (Vm) and input resistance of the cell membrane (Ri) are depolarized and increased by JTT-608, respectively. The apparent transference number for K+ was also significantly decreased after the addition of JTT-608. These effects immediately occurred after addition of JTT-608 and very rapidly disappeared after removal of JTT-608, which has not been observed in sulfonylureas. Also, these effects of JTT-608 were diminished, but not completely by diazoxide. JTT-608 did not affect the specific binding of [3H]glibenclamide to the sulfonylurea receptor. These findings suggest that JTT-608 mainly inhibits ATP-sensitive K+ channel activity via a binding site distinct from the sulfonylurea receptor and then depolarizesVm to open voltage-dependent L-type Ca2+ channels. Subsequently, these events stimulate Ca2+ entry to increase [Ca2+]i and induce insulin secretion from MIN6 cells. Therefore, JTT-608 is a unique hypoglycemic agent that enhances high glucose-induced insulin secretion. The present findings indicate that JTT-608 is a more useful new class of therapeutic drug for patients with non-insulin-dependent diabetes mellitus, compared with sulfonylurea derivatives. The American Society for Pharmacology and Experimental Therapeutics ER -