JTT-608 controls blood glucose by enhancement of glucose-stimulated insulin secretion in normal and diabetes mellitus rats

We investigated the pharmacological effects of a new anti-hyperglycemic age nt, JTT-608 [trans-4-(4-methylcydohexyl)-4-oxobutyric acid], in normal and neonatally streptozotocin-treated rats. In normal rats, JTT-608 improved gl ucose tolerance at 3-30 mg/kg, doses that did not cause a decrease in fasti ng blood glucose levels. In contrast, tolbutamide (10-100 mg/kg) and gliben clamide (1-3 mg/kg) caused a persistent decrease in fasting blood glucose l evels, and tolbutamide only improved glucose tolerance at 10-100 mg/kg. Fur thermore, JTT-608 (3-30 mg/kg) enhanced insulin secretion only with glucose stimulation, but tolbutamide (10-100 mg/kg) enhanced it both with and with out glucose stimulation. In neonatally streptozotocin-treated rats, JTT-608 (10-100 mg/kg) improved glucose tolerance with enhanced insulin secretion in the oral glucose tolerance test and meal tolerance test. Additionally, J TT-608 improved glucose tolerance dose dependently, but the effect of tolbu tamide reached a plateau. We conclude that JTT-608 is an enhancer of glucos e-stimulated insulin secretion. (C) 1999 Elsevier Science B.V. All rights r eserved.