A novel dipeptidyl peptidase-4 inhibitor, alogliptin (SYR-322), is effective in diabetic rats with sulfonylurea-induced secondary failure.
OBJECTIVE
Loss of efficacy over time or secondary failure occurs somewhat often and remains a major concern of sulfonylurea (SU) therapy. In this study, we investigated the benefits of alogliptin, an oral, potent and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor, in a rat model exhibiting SU secondary failure.


METHODS
Neonatally streptozotocin-induced diabetic rats (N-STZ-1.5 rats), a non-obese model of type 2 diabetes, were used in these studies. The effects of alogliptin on DPP-4 activity and glucagon-like peptide 1 (GLP-1) concentration were determined by measuring their levels in plasma. In addition, the effects of alogliptin on an oral glucose tolerance test were investigated by using an SU secondary failure model.


RESULTS
Alogliptin dose dependently suppressed plasma DPP-4 activity leading to an increase in the plasma active form of GLP-1 and improved glucose excursion in N-STZ-1.5 rats. Repeated administration of glibenclamide resulted in unresponsiveness or loss of glucose tolerance typical of secondary failure. In these rats, alogliptin exhibited significant improvement of glucose excursion with significant increase in insulin secretion. By contrast, glibenclamide and nateglinide had no effect on the glucose tolerance of these rats.


CONCLUSIONS
The above findings suggest that alogliptin was effective at improving glucose tolerance and therefore overcoming SU induced secondary failure in N-STZ-1.5 rats.
Asakawa
Tomoko
T
Pharmaceutical Research Laboratories I, Pharmaceutical Research Division, Takeda Pharmaceutical Company LTD., Osaka, Japan. Asakawa_Tomoko@takeda.co.jp
Moritoh
Yusuke
Y
Kataoka
Osamu
O
Suzuki
Nobuhiro
N
Takeuchi
Koji
K
Odaka
Hiroyuki
H
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4 / Q000097:blood; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D010880:Piperidines / Q000627:therapeutic use*; D051381:Rats; D013453:Sulfonylurea Compounds / Q000627:therapeutic use; D017211:Treatment Failure; D014498:Uracil / Q000031:analogs & derivatives* / Q000627:therapeutic use
D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D010880:Piperidines; D013453:Sulfonylurea Compounds; D014498:Uracil; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4; C520853:alogliptin