Effects of the dipeptidyl peptidase-IV inhibitor ASP8497 on glucose tolerance in animal models of secondary failure.
Sulfonylureas promote insulin secretion and potently lower blood glucose levels, however, they induce hypoglycemia and undergo a reduction in efficacy when administered long-term (secondary failure). The dipeptidyl peptidase (DPP)-IV inhibitor ASP8497, (2S,4S)-4-fluoro-1-({[4-methyl-1-(methylsulfonyl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrile monofumarate, inhibits the degradation of glucagon-like peptide-1 (GLP-1), an incretin hormone, and promotes insulin secretion in a glucose-dependent manner. ASP8497 is therefore less likely to induce hypoglycemia and less likely to show reduced efficacy even after repeated administration. Here, to determine whether or not ASP8497 improves glucose tolerance in Zucker fatty rats, we examined the effects of ASP8497 and gliclazide, a sulfonylurea, on glucose tolerance after repeated administration. We also developed an animal model of secondary failure using streptozotocin-nicotinamide-induced diabetic mice.


RESULTS
ASP8497 (3mg/kg) improved glucose intolerance in Zucker fatty rat without any attenuation (blood glucose AUC: P=0.034 vs. vehicle) while gliclazide (10mg/kg) did not (P=0.916 vs. vehicle). Furthermore, ASP8497 (3, 10mg/kg) was found to effect glucose tolerance dose-dependently (3mg/kg: P=0.230, 10mg/kg: P=0.003 vs. glibenclamide (10mg/kg)) by enhancing insulin secretion in mice inadequately controlled with glibenclamide. Our results suggest that ASP8497 may be effective even in patients with secondary failure who are unable to maintain satisfactory glycemic control using sulfonylureas.
Someya
Yuka
Y
Applied Pharmacology Research Labs, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, Japan. yuka.hayashizaki@jp.astellas.com
Nakano
Ryosuke
R
Tahara
Atsuo
A
Takasu
Toshiyuki
T
Takeuchi
Asako
A
Nagase
Itsuro
I
Matsuyama-Yokono
Akiko
A
Hayakawa
Masahiro
M
Sasamata
Masao
M
Miyata
Keiji
K
Uchiyama
Yasuo
Y
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000097:blood / Q000473:pathology / Q000628:therapy; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005951:Glucose Tolerance Test; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D013453:Sulfonylurea Compounds / Q000627:therapeutic use; D017211:Treatment Failure
C530746:4-fluoro-1-(((4-methyl-1-(methylsulfonyl)piperidin-4-yl)amino)acetyl)pyrrolidine-2-carbonitrile; D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D010880:Piperidines; D011759:Pyrrolidines; D013453:Sulfonylurea Compounds