Evaluation of the antidiabetic effects of dipeptidyl peptidase-IV inhibitor ASP8497 in streptozotocin-nicotinamide-induced mildly diabetic mice.
Gastrointestinal hormone glucagon-like peptide-1 (GLP-1) has a potent glucose-dependent insulinotropic effect and is rapidly degraded by dipeptidyl peptidase (DPP)-IV. Therefore, the use of DPP-IV inhibitors is being actively explored as a novel approach to the treatment of type 2 diabetes. The present study investigated the antidiabetic effects of the DPP-IV inhibitor ASP8497 in streptozotocin-nicotinamide-induced mildly diabetic mice which possess aggravation of glucose tolerance due to loss of early-phase insulin secretion. ASP8497 exhibited good oral bioavailability with potent inhibition of plasma DPP-IV activity. This inhibitory activity lasted up to 24 h when administered at 5 mg/kg twice a day or 10 mg/kg once a day. A single oral administration of ASP8497 (0.3-3 mg/kg) significantly improved glucose tolerance by increasing plasma insulin and GLP-1 levels during the oral glucose or liquid meal tolerance tests. These effects were seen not only immediately, but also 8 h after administration. In contrast, ASP8497 (0.3-10 mg/kg) had no significant effect on blood glucose and plasma insulin levels under fasting conditions. Furthermore, repeated administration of ASP8497 (5 mg/kg twice a day or 10 mg/kg once a day) for 25 days significantly decreased nonfasting blood glucose and HbA(1c) levels. These results suggest that ASP8497 is a potent and long-acting DPP-IV inhibitor that improves glucose tolerance through glucose-dependent insulinotropic action via the elevation of the GLP-1 level in streptozotocin-nicotinamide-induced mildly diabetic mice. It is expected to be useful as a therapeutic agent for impaired glucose tolerance and type 2 diabetes.
Tahara
Atsuo
A
Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Japan. atsuo.tahara@jp.astellas.com
Matsuyama-Yokono
Akiko
A
Nakano
Ryosuke
R
Someya
Yuka
Y
Hayakawa
Masahiko
M
Shibasaki
Masayuki
M
D000284:Administration, Oral; D000818:Animals; 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; D004353:Drug Evaluation, Preclinical; D005215:Fasting; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000032:analysis; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010179:Pancreas / Q000737:chemistry; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*
D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D007328:Insulin; D010880:Piperidines; D011759:Pyrrolidines; C530746:4-fluoro-1-(((4-methyl-1-(methylsulfonyl)piperidin-4-yl)amino)acetyl)pyrrolidine-2-carbonitrile