Antidiabetic effects of dipeptidyl peptidase-IV inhibitors and sulfonylureas in streptozotocin-nicotinamide-induced mildly diabetic mice.

Abstract

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.

• Authors: Akiko Matsuyama-Yokono, Atsuo Tahara, Ryosuke Nakano, Yuka Someya, Katsuhisa Shiraki, Masahiko Hayakawa, Masayuki Shibasaki
• Journal: Metabolism: clinical and experimental (Metabolism) Vol. 58 Issue 3 Pg. 379-86 (Mar 2009) ISSN: 1532-8600 [Electronic] United States
• PMID: 19217455 (Publication Type: Journal Article)

Chemical References

• 4-fluoro-1-(((4-methyl-1-(methylsulfonyl)piperidin-4-yl)amino)acetyl)pyrrolidine-2-carbonitrile
• Blood Glucose
• Dipeptidyl-Peptidase IV Inhibitors
• Hypoglycemic Agents
• Insulin
• Piperidines
• Pyrrolidines
• Sulfonylurea Compounds
• Niacinamide
• Glucagon-Like Peptide 1
• Gliclazide
• Glyburide

Topics

• Animals
• Blood Glucose (drug effects, metabolism)
• Diabetes Mellitus, Experimental (drug therapy)
• Diabetes Mellitus, Type 2 (drug therapy)
• Dipeptidyl-Peptidase IV Inhibitors (therapeutic use)
• Gliclazide (therapeutic use)
• Glucagon-Like Peptide 1 (blood)
• Glucose Intolerance (drug therapy)
• Glyburide (therapeutic use)
• Hypoglycemic Agents (therapeutic use)
• Insulin (blood)
• Male
• Mice
• Mice, Inbred ICR
• Niacinamide
• Piperidines (therapeutic use)
• Pyrrolidines (therapeutic use)
• Sulfonylurea Compounds (therapeutic use)