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.
Furukawa
N
N
Japan Tobacco, Central Pharmaceutical Research Institute, Takatsuki, Osaka.
Ohta
T
T
Noguchi
T
T
Yonemori
F
F
Wakitani
K
K
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002087:Butyrates / Q000494:pharmacology*; D002460:Cell Line; D003510:Cyclohexanes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005947:Glucose / Q000378:metabolism*; D005905:Glyburide / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013311:Streptozocin / Q000494:pharmacology
D001786:Blood Glucose; D002087:Butyrates; D003510:Cyclohexanes; D007004:Hypoglycemic Agents; D007328:Insulin; D013311:Streptozocin; D005947:Glucose; D005905:Glyburide; C116719:4-(4-methylcyclohexyl)-4-oxobutyric acid