Dipeptidyl peptidase IV inhibition improves impaired glucose tolerance in high-fat diet-fed rats: study using a Fischer 344 rat substrain deficient in its enzyme activity.
This study was performed to determine the effects of a high-fat diet on glucose metabolism after an oral glucose challenge in high-fat diet-fed dipeptidyl peptidase IV (DPP-IV) positive (+) and deficient (-) Fischer 344 (F344) rats and the effects of novel DPP-IV inhibitor NVP-DPP728 (1-[2-[(5-cyanopyridin-2-yl)amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidine monohydrochloride salt) on glucose tolerance in high-fat diet-fed F344 rats. In DPP-IV(+) rats, a high-fat diet load caused impaired glucose tolerance, such as increases of plasma insulin and blood glucose concentrations after oral glucose challenge, compared with a standard chow-fed group. In contrast, no marked change in glucose tolerance was induced by the high-fat diet in DPP-IV(-) rats. Blood glucose concentrations in DPP-IV(-) rats after glucose challenge were significantly lower than in DPP-IV(+) rats under high-fat diet load conditions. In standard chow and high-fat diet-fed DPP-IV(+) rats, NVP-DPP728 significantly suppressed glucose excursions after glucose challenge by inhibiting the plasma DPP-IV activity, associated with the stimulation of early insulin secretion. NVP-DPP728 did not affect glucose tolerance in DPP-IV(-) rats under both conditions. These results indicate that the amelioration of glucose tolerance by NVP-DPP728 in DPP-IV(+) rats was directly due to the inhibition of plasma DPP-IV activity, which might be via the subsequent increase in endogenous incretin action.
Mitani
Hironobu
H
Research Division, Tsukuba Research Institute, Novartis Pharma K.K., Japan. hironobu.mitani@pharma.novartis.com
Takimoto
Misato
M
Hughes
Thomas E
TE
Kimura
Masaaki
M
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; 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; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013997:Time Factors
C121834:1-(((2-((5-cyanopyridin-2-yl)amino)ethyl)amino)acetyl)-2-cyano-(S)-pyrrolidine; D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D008055:Lipids; D009570:Nitriles; D011480:Protease Inhibitors; D011759:Pyrrolidines; D018819:Dipeptidyl Peptidase 4