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

Abstract

ABSTRACT-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 dietfed 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.

Acute and chronic administration of SHR117887, a novel and specific dipeptidyl peptidase-4 inhibitor, improves metabolic control in diabetic rodent models

“…A single oral dose of 3, 10, and 30 mg/kg SHR117887 inhibited serum DPP-4 activity by 84%, 91%, and 93%, respectively, at 2 h postdose, reducing serum glucose AUC 0-120 min by 30.2%, 35.0%, and 40.6%, respectively. LAF237 showed a similar pharmacological effect to SHR117887, and these findings are consistent with the previous reports using other DPP-4 inhibitors in glucose-intolerant rodents, including high-fat-fed rats [26,28] , Zucker fatty rats [30,31] and mice [32] . These results suggest that SHR117887 improves glucose tolerance through the elevation of serum insulin and active GLP-1 levels via the inhibition of DPP-4 activity in normal and diabetic animal models, but the achievable glucose lowering effect seems to be correlated with the degree of insulin resistance in different animal models.…”

“…We therefore further investigated the acute pharmacological effect of SHR117887 in the DIO rat, a model with modest insulin resistance and glucose intolerance [28] . The minimum effective dose of SHR117887 to augment the peak value of active GLP-1 and GLP-1 AUC 0-60 min was 3 mg/kg, which is also the minimum effective dose to increase the insulin peak value in 15 min after glucose loading.…”

The role of gut hormones in glucose homeostasis

“…The importance of DPP4 for glucose homeostasis is revealed in studies characterizing the phenotype of DPP4-deficient rodents. DPP4-deficient rats exhibit elevated levels of GLP1 and improved glucose tolerance (94), and DPP4-deficient mice exhibit increased levels of plasma GLP1 and GIP (95), enhanced insulin secretion, improved glucose tolerance, and resistance to diet-induced obesity.…”

Dipeptidyl Peptidase-IV Inhibitory Activity of Peptides in Porcine Skin Gelatin Hydrolysates

“…This finding that over 95% of the degradation of GLP-1 is attributed to the action of DPP-IV led to an elevated interest in inhibition of this enzyme for the treatment of type 2 diabetes [15]. Some previous studies have shown that specific DPP-IV inhibition increased the half-life of total circulating GLP-1, decreased plasma glucose, and improved impaired glucose tolerance in animal and human experiments [16][17][18].…”

“…There are several chemical compounds used in vitro and in animal models to inhibit DPP-IV activity, such as Val-pyrrolidide [17], NVP-DPP728 [18], Lys[Z(NO2)]-thiazolidide and Lys[Z(NO2)]-pyrrolidide [19]. However, such chemical compounds, which often have to be administered by injection, may result in side effects as chemical drugs often do.…”