Antidiabetic effect of chronic administration of JTT-608, a new hypoglycemic agent, in diabetic Goto–Kakizaki rats

Abstract

We investigated the chronic effect of a new antidiabetic agent, trans-4-(methylcyclohexyl)-4-oxobutyric acid (JTT-608), in Goto–Kakizaki rats, a genetic model of non-obese type II diabetes mellitus. The rats were fed a liquid meal, three times a day, for 12 weeks. The rats were treated orally with JTT-608 (10–100 mg/kg) 10 min before each meal. Fasting blood glucose, triglyceride and hemoglobin A1c levels were reduced by JTT-608 at all dose levels during the experimental period. Blood glucagon-like peptide-1 level with 100 mg/kg JTT-608 increased at the end of the treatment period. JTT-608 (30–100 mg/kg) reduced urinary protein levels after administration for 5–12 weeks. In Goto–Kakizaki rats showing slight diabetic renal lesions, pathological examination revealed that JTT-608 reduced the incidence of vacuolation in renal tubules. JTT-608 (30–100 mg/kg) ameliorated the reduced motor nerve conduction velocities observed in the Goto–Kakizaki rats after administration for 12 weeks. We conclude that chronic administration of JTT-608 produces good blood glucose control and gradually arrests the development of diabetic neuropathy and nephropathy.