Glucose-dependent insulinotropic effects of JTT-608, a novel antidiabetic compound.

The effects of JTT-608 [trans-4-(4-methylcyclohexyl)-4-oxobutyric acid], a novel antidiabetic compound, on insulin secretion were investigated using mouse insulinoma cell line (MIN6 cells) and isolated, perfused rat pancreas. JTT-608 enhanced insulin secretion in MIN6 cells in a dose dependent (10-300 microM) and glucose concentration-dependent (2.8-16.7 mM) manner. Unlike sulphonylureas, JTT-608 minimally stimulated insulin secretion at low glucose concentrations but potently enhanced insulin secretion at high glucose concentrations. In isolated, perfused pancreas of normal rats, JTT-608 (100-300 microM) dose-dependently enhanced insulin secretion in the first and second phases at high glucose concentrations but minimally stimulated insulin secretion at a basal glucose concentration. In isolated, perfused pancreas of neonatally streptozotocin-induced non-insulin-dependent diabetes mellitus rats (nSTZ rats), JTT-608 (200 microM) normalized the first phase and doubled the second phase of insulin secretion. In MIN6 cells, JTT-608 did not inhibit the binding of [3H]glibenclamide to membrane fractions but enhanced K+-ATP channel-independent insulin secretion. These results suggest that JTT-608 enhances insulin secretion in a different manner and via a different mechanism from hypoglycemic sulphonylureas.