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.