Antidiabetic effects of dipeptidyl peptidase-IV inhibitors and sulfonylureas in streptozotocin-nicotinamide-induced mildly diabetic mice.
The present study investigated the antidiabetic effects of the dipeptidyl peptidase (DPP)-IV inhibitors ASP8497 and vildagliptin, and the sulfonylureas glibenclamide and gliclazide in streptozotocin-nicotinamide-induced mildly diabetic mice. A single administration of ASP8497 and vildagliptin significantly improved glucose tolerance by increasing plasma insulin and glucagon-like peptide-1 levels. In addition, a single administration of glibenclamide and gliclazide also caused significant improvement in glucose tolerance with an accompanying increase in the plasma insulin level. Subsequently, the effects of a 1-week chronic daily dosing of DPP-IV inhibitors and sulfonylureas were investigated. All drugs significantly improved glucose tolerance on day 1 of chronic daily dosing. After 1 week of chronic daily dosing, the DPP-IV inhibitors caused a significant improvement in glucose tolerance similar to those observed on day 1 by increasing the plasma insulin and glucagon-like peptide-1 levels. In contrast, the sulfonylureas had no significant improving or insulinotropic effect. Furthermore, ASP8497 also had an antihyperglycemic effect and improved pancreatic histopathologic lesions in a 4-week chronic daily dosing study. These results suggest that chronic daily dosing of sulfonylureas had virtually no antidiabetic effects because of marked attenuation of the insulinotropic action in streptozotocin-nicotinamide-induced mildly diabetic mice. In contrast, the antidiabetic efficacy of DPP-IV inhibitors, including ASP8497, did not change even after chronic daily dosing; therefore, DPP-IV inhibitors are useful as a therapeutic agent for impaired glucose tolerance and type 2 diabetes mellitus.
Matsuyama-Yokono
Akiko
A
Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 300-2698, Japan.
Tahara
Atsuo
A
Nakano
Ryosuke
R
Someya
Yuka
Y
Shiraki
Katsuhisa
K
Hayakawa
Masahiko
M
Shibasaki
Masayuki
M
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D005907:Gliclazide / Q000627:therapeutic use; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D018149:Glucose Intolerance / Q000188:drug therapy; D005905:Glyburide / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009536:Niacinamide; D010880:Piperidines / Q000627:therapeutic use; D011759:Pyrrolidines / Q000627:therapeutic use; D013453:Sulfonylurea Compounds / Q000627:therapeutic use
C530746:4-fluoro-1-(((4-methyl-1-(methylsulfonyl)piperidin-4-yl)amino)acetyl)pyrrolidine-2-carbonitrile; D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D010880:Piperidines; D011759:Pyrrolidines; D013453:Sulfonylurea Compounds; D009536:Niacinamide; D052216:Glucagon-Like Peptide 1; D005907:Gliclazide; D005905:Glyburide