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- Title
Chronic Administration of Alogliptin (SYR-322), a Novel Dipeptidyl Peptidase-IV Inhibitor, Improved Beta-Cell Function in ob/ob Mice.
- Authors
Moritoh, Yusuke; Takeuchi, Koji; Kataoka, Osamu; Asakawa, Tomoko; Odaka, Hiroyuki
- Abstract
Alogliptin (SYR-322) is a novel, oral, potent, and highly selective dipeptidyl peptidase-IV (DPP-4) inhibitor under development as a once-daily treatment for type 2 diabetes (T2D). The efficacy of alogliptin was investigated in ob/ob mice, an obese model of T2D. Chronic administration of alogliptin (2.8 and 14.1 mg/kg/day, admixture with diet) for 4 weeks dose dependently inhibited plasma DPP-4 activity (24% and 62%, respectively) and significantly increased active glucagon-like peptide-1 (2.3- and 5.3-fold, respectively). In addition, decreased glycosylated hemoglobin (0.4% and 0.7%, respectively), increased plasma insulin (1.5- and 1.8-fold, respectively), increased pancreatic insulin content (1.5- and 1.9-fold, respectively), decreased glucagon (26% and 23%, respectively), and significantly decreased plasma triglycerides (51% and 42%, respectively) were observed. In a second study, the effects of a higher dose of alogliptin on glucose tolerance and beta-cell function were investigated in ob/ob mice (42.2 mg/kg/day, admixture with diet). After 4 weeks, plasma DPP-4 activity was significantly decreased (80%), glycosylated hemoglobin was significantly decreased (0.9%), and plasma insulin (2-fold) and pancreatic insulin content (2.5-fold) were significantly increased. After the 4 weeks of dosing, the mice were fasted and subjected to an oral meal tolerance test. Despite the lack of measurable plasma DPP-4 inhibition before the test, significantly increased early phase insulin secretion (2.4-fold) and improved glucose tolerance (25% decrease in glucose AUC) were observed in the alogliptin-treated mice. Immunohistochemical analysis revealed increased insulin staining in the beta-cells of alogliptin-treated mice compared with non-treated ob/ob mice, suggestive of improved beta-cell function. No significant changes in body weight or food consumption were observed in alogliptin-treated mice during the 2 studies. Taken together, these results suggest that alogliptin treatment may result in effective glycemic control and beta-cell preservation in patients with T2D.
- Subjects
DRUG efficacy; CD26 antigen; TYPE 2 diabetes; GLUCAGON-like peptide 1; INSULIN; CELL physiology; BODY weight
- Publication
Diabetes, 2007, Vol 56, pA136
- ISSN
0012-1797
- Publication type
Article