Antidiabetic effects of CS-045 were evaluated in 5-month-old C 57 BL KsJ-db db mice (db db). CS-045 administered for 3 weeks to diabetic db db mice as a 0.2% food admixture improved hyperglycemia (855±25 v 298±62 mg/dL, P<. 01) and glucose intolerance, and lowered plasma triglyceride (299.6±28.7 v 76.3±20.7 mg/dL, P<. 01) and free fatty acid (FFA) levels (1.16±0.14 v 0.57±0.07 mEq/L, P<. 01). Food intake was not changed, while a small but significant increase in body weight was observed in CS-045-treated mice. Plasma insulin levels gradually increased after 5 days of CS-045 treatment, and a nonsignificant increase was observed in plasma insulin levels after 3 weeks (1.85±0.50 v 4.54±1.47 mg/mL). In contrast, the plasma glucagon levels decreased after 3 weeks of CS-045 treatment. Histological examination by aldehyde-fucshin staining demonstrated that pancreatic β cells in CS-045-treated db db mice were heavily regranulated, whereas most of the β cells were extensively degranulated in nontreated db db mice. The heavily regranulated state of β cells was also compatible with an increase in pancreatic insulin content in CS-045-treated db db mice. Electron microscopic analysis showed a well-developed endoplasmic reticulum and the accumulation of much amorphous structural material in the intracisternal space of β cells from CS-045-treated db db mice, which were suggestive of an increase in insulin synthesis. Moreover, CS-045 treatment decreased exocrine-containing islets, which was associated with the islets' degeneration process. Immunohistochemical staining of islets showed that CS-045 treatment normalized the distribution pattern of endocrine cells in the islets of db db mice, reflected by a predominantly peripheral location of α and δ cells. These results show that even at a late state in db db mice, CS-045 treatment improves severe hyperglycemia. At the cellular level, treatment improved the degranulation and synthesis of insulin in pancreatic β cells, as well as the distribution of endocrine cells in the islets.