The hypoglycemic effect of To-Kai-San (TS) was studied in normal mice, streptozotocin-induced diabetic mice, one of the animal models of insulin-dependent diabetes mellitus (IDDM) with hypoinsulinemia, and KK-Ay mice, one of the animal models of non-insulin-dependent diabetes mellitus (NIDDM) with hyperinsulinemia. TS (1,500 mg/kg) reduced the blood glucose of the KK-Ay mice from 441 +/- 36 to 285 +/- 52 mg/100 ml 7 h after a single oral administration (p < 0.001). However, no changes in blood glucose were observed in the normal and STZ-induced diabetic mice. TS also decreased the blood glucose 20 days after repeated administration to normal and KK-Ay mice. In addition, TS-treated KK-Ay mice showed decreased plasma insulin levels after both single and repeated administration. From these findings, it is believed that TS may require the presence of insulin to display its activity.