Characterization of CS-045, A New Oral Antidiabetic Agent, II. Effects on Glycemic Control and Pancreatic Islet Structure at a Late Stage of the Diabetic Syndrome in C57BL/KsJ-db/db Mice

Antidiabetic effects of CS-045 were evaluated in 5-month-old C57BLKsJ-dbdb mice (dbdb). CS-045 administered for 3 weeks to diabetic dbdb 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 dbdb mice were heavily regranulated, whereas most of the β cells were extensively degranulated in nontreated dbdb mice. The heavily regranulated state of β cells was also compatible with an increase in pancreatic insulin content in CS-045-treated dbdb 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 dbdb 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 dbdb mice, reflected by a predominantly peripheral location of α and δ cells. These results show that even at a late state in dbdb 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.