Inhibition of Hepatic Glucose Production by SDZ 51641

The new oral hypoglycemic agent SDZ 51641 was evaluated in nondiabetic rats and a rat model of human non-insulin-dependent diabetes mellitus. Diabetes was induced with a single injection of 37.5 mg/kg streptozocin, and the rats exhibited hyperglycemia in the fed state with normal insulin levels. Treatment of nondiabetic animals with 100 mg/kg SDZ 51641 given orally significantly decreased serum glucose and ketone levels within 4 h without affecting insulin levels. Nonesterified fatty acids increased more than twofold during the same period. Its effect on ketone and fatty acid levels suggests that SDZ 51641 acts as an inhibitor of fatty acid oxidation. Diabetic rats treated with SDZ 51641 exhibited a significant acute hypoglycemic response, which was more pronounced after 3 days of treatment. The compound also significantly decreased serum cholesterol and triglyceride levels 27 and 53%, respectively. When endogenous hepatic glucose production was assessed in nondiabetic and diabetic animals via continuous infusion of [3-³H]glucose, we found that hepatic glucose production was elevated 43% in diabetic compared with control animals. When diabetic rats were treated with 100 mg/kg SDZ 51641, hepatic glucose production decreased to normal levels within 6 h. Hyperinsulinemic-euglycemic clamp studies indicated that SDZ 51641 had no effect on insulinstimulated glucose utilization. Measurement of [1-¹⁴C]oleate oxidation in isolated hepatocytes demonstrated that SDZ 51641 inhibited long-chain fatty acid oxidation in a concentration-dependent manner. The compound was ineffective at inhibiting longchain fatty acid oxidation in epitrochlearis or soleus muscles. In summary, SDZ 51641 is a new oral hypoglycemic agent that is very effective in decreasing blood glucose levels in nondiabetic and diabetic rats. This is accomplished at least partially by inhibition of hepatic glucose production in vivo, with no effect on peripheral glucose utilization. In addition, the ability of SDZ 51641 to decrease serum ketone, cholesterol, and triglyceride levels suggests that inhibition of hepatic glucose production is linked to inhibition of fatty acid oxidation.