Vol. 297, Issue 3, 953-960, June 2001

A Novel Enhancer of Insulinotrophic Action by High Glucose (JTT-608) Stimulates Insulin Secretion from Pancreatic -Cells via a New Cellular Mechanism

Naoki Itabashi, Koji Okada, Shigeaki Muto, Nobuya Fujita, Takeshi Ohta, Jun-ichi Miyazaki, Yasushi Asano and Toshikazu Saito

Division of Endocrinology and Metabolism (N.I., K.O., N.F., T.S.) and Nephrology (S.M., Y.A.), Department of Medicine, Jichi Medical School, Minamikawachi Tochigi, Japan; Central Pharmaceutical Research Institute, Japan Tobacco, Inc., Osaka, Japan (T.O.); and Department of Nutrition and Physiological Chemistry, Osaka University Medical School, Osaka, Japan (J.M.)

Insulin secretion from MIN6 cells (a pancreatic -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 (V_m) and input resistance of the cell membrane (R_i) 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 depolarizes V_m 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.