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

The Japanese Journal of Pharmacology

Hironobu Mitani¹  Misato Takimoto¹  Thomas E. Hughes²  Masaaki Kimura¹ 

[1] Research Division, Tsukuba Research Institute, Novartis Pharma K.K.;Novartis Institute for Biomedical Research

关键词: Dipeptidyl peptidase IV;    Fischer 344 rat;    Glucose tolerance;    High-fat diet;    Diabetes;   

DOI  :  10.1254/jjp.88.442

学科分类：药理学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(34)Cited-By(35)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.

【 授权许可】

Unknown