title: Dipeptidyl peptidase IV inhibitor NVP-DPP728 ameliorates early insulin response and glucose tolerance in aged rats but not in aged Fischer 344 rats lacking its enzyme activity.
abstract: The aim of this study was to investigate the effects of aging on glucose metabolism after oral glucose challenge in aged dipeptidyl peptidase IV (DPP-IV) positive (+) Fischer 344 (F344), DPP-IV deficient (-) F344 and DPP-IV(+) Wistar rats and to determine the effect of a DPP-IV inhibitor NVP-DPP728 (1-[2-[(5-cyanopyridin-2-yl)amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidine monohydrochloride salt) on glucose tolerance in aged rats. Aging caused a decrease in early insulin response after an oral glucose challenge in aged Wistar or DPP-IV(+) F344 rats, but not in aged DPP-IV(-) F344 rats, compared with young control groups. Glucose tolerance after an oral glucose challenge in aged DPP-IV(-) F344 rats was better than in aged DPP-IV(+) F344 and Wistar rats associated with the preservation of the early insulin response. NVP-DPP728 improved the glucose tolerance after an oral glucose challenge by potentiating the early insulin response throughout the inhibition of plasma DPP-IV activity in aged DPP-IV(+) Wistar and F344 rats. In contrast, NVP-DPP728 did not affect the glucose tolerance after an oral glucose challenge in aged DPP-IV(-) F344 rats. These results indicate that treatment with NVP-DPP728 ameliorated glucose tolerance in aged rats by the direct inhibition of plasma DPP-IV activity and presumably the subsequent increase in endogenous incretin action.
authors.affiliation: Research Division, Tsukuba Research Institute, Novartis Pharma K.K., Japan. hironobu.mitani@pharma.novartis.com
authors.forename: Hironobu
authors.initials: H
authors.lastname: Mitani
authors.forename: Misato
authors.initials: M
authors.lastname: Takimoto
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kimura
mesh_terms: D000284:Administration, Oral; D000375:Aging / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D018819:Dipeptidyl Peptidase 4 / Q000097:blood*; D018149:Glucose Intolerance / Q000201:enzymology*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood*; D008055:Lipids / Q000097:blood; D009570:Nitriles / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar
chemical_list: C121834:1-(((2-((5-cyanopyridin-2-yl)amino)ethyl)amino)acetyl)-2-cyano-(S)-pyrrolidine; D001786:Blood Glucose; D007328:Insulin; D008055:Lipids; D009570:Nitriles; D011480:Protease Inhibitors; D011759:Pyrrolidines; D018819:Dipeptidyl Peptidase 4