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

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.

(R)-8-(3-Amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a Novel Xanthine-Based Dipeptidyl Peptidase 4 Inhibitor, Has a Superior Potency and Longer Duration of Action Compared with Other Dipeptidyl Peptidase-4 Inhibitors

“…These findings agree with earlier studies using other DPP-4 inhibitors in glucose-intolerant rodents, including Zucker fatty rats (Balkan et al, 1999), high-fat-fed rats (Mitani et al, 2002a), and mice (Ahrén et al, 2000), and aged rats (Mitani et al, 2002b). Our observations go further than others in that we prove the effect up to 24 h after administration of BI 1356.…”

Acute and Chronic Effects of the Incretin Enhancer Vildagliptin in Insulin-Resistant Rats

“…The minimum effective dose of vildagliptin to inhibit DPP-4, to augment intact GLP-1, to improve ␤-cell function, and to reduce glucose excursions was 0.3 mg/kg, and a dose of 3 mg/kg exerted maximal effects on all parameters. These findings are consistent with those of several earlier studies using other DPP-4 inhibitors in glucose intolerant rodents, including Zucker fatty rats (Pederson et al, 1998;Balkan et al, 1999), high-fat-fed rats (Mitani et al, 2002a) and mice (Ahrén et al, 2000), and aged rats (Mitani et al, 2002b), although no previous studies reported on the dose-response characteristics of DPP-4 inhibitors.…”

Dipeptidyl Peptidase-4 Inhibition and the Treatment of Type 2 Diabetes

“…Verification that DPP-4 was the dominant molecular target for the glucose lowering properties of NVP-DPP728 was illustrated in studies demonstrating that this compound acutely lowered blood glucose following oral glucose challenge in wild-type Wistar rats but not in Fischer 344 rats with an inactivating mutation in the DPP-4 gene (27). Nevertheless, DPP-4 inhibition is not capable of exerting significant antidiabetic actions in all preclinical models, as acute VP administration increased plasma levels of intact GLP-1 in older db/db mice but VP did not lower blood glucose in 24-week-old severely hyperglycemic (fasting blood glucose 29 mmol/l) db/db mice (28).…”