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

摘要

Insulin secretion from MIN6 cells (a pancreatic #beta#-cell line) in- duced 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 sulfonyl- urea). 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 demon- strated that membrane potential (V m) and input resistance of the cell membrane (RJ 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 rH]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 Vm to open voltage-dependent L-type Ca2+ chan- nels. Subsequently, these events stimulate Ca2+ entry to in- crease [Ca2+]i and induce insulin secretion from MIN6 cells. Therefore, JTT -608 is a unique hypoglycemic agent that en- hances 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 dia- betes mellitus, compared with sulfonylurea derivatives.