A novel enhancer of insulinotrophic action by high glucose (JTT-608) stimulates insulin secretion from pancreatic beta-cells via a new cellular mechanism.

Insulin secretion from MIN6 cells (a pancreatic beta-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 Ca(2+)-free condition, a L-type Ca(2+) channel blocker (nifedipine) and an ATP-sensitive K(+) channel opener, diazoxide, completely inhibited increases in cytosolic free Ca(2+) ([Ca(2+)]i) and insulin secretion evoked by JTT-608 in the presence of extracellular Ca(2+). 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 [(3)H]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 Ca(2+) channels. Subsequently, these events stimulate Ca(2+) entry to increase [Ca(2+)]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.