Inhibition of dipeptidyl peptidase IV with NVP-DPP728 increases plasma GLP-1 (7-36 amide) concentrations and improves oral glucose tolerance in obese Zucker rats

Aims/hypothesis: The potent incretin hormone glucagon-like peptide 1 (GLP-1) plays a pivotal role in prandial Insulin secretion. In the circulation GLP-1 (7-36) amide is, however, rapidly (t(1/2):1-2 min) inactivated by the protease Dipeptidyl Peptidase IV (DPP-IV). We therefore investigated whether DPP-IV inhibition is a feasible approach to improve glucose homeostasis in Insulin resistant, glucose intolerant fatty Zucker rats, a model of mild Type II (non-insulin-dependent) diabetes mellitus.

Methods: An oral glucose tolerance test was done in lean and obese male Zucker rats while plasma DPP-IV was inhibited by the specific and selective inhibitor NVP-DPP728 given orally.

Results: Inhibition of DPP-IV resulted in a significantly amplified early phase of the Insulin response to an oral glucose load in obese fa/fa rats and restoration of glucose excursions to normal. In contrast, DPP-IV inhibition produced only minor effects in lean FA/? rats. Inactivation of GLP-1 (7-36) amide was completely prevented by DPP-IV inhibition suggesting that the effects of this compound on oral glucose tolerance are mediated by increased circulating concentrations of GLP-1 (7-36) amide. Reduced gastric emptying, as monitored by paracetamol appearance in the circulation after an oral bolus, did not appear to have contributed to the reduced glucose excursion.

Conclusion/interpretation: It is concluded that NVP-DPP728 inhibits DPP-IV and improves Insulin secretion and glucose tolerance, probably through augmentation of the effects of endogenous GLP-1. The improvement observed in prandial glucose homeostasis during DPP-IV inhibition suggests that inhibition of this Enzyme is a promising treatment for Type II diabetes. [Diabetologia (1999) 42: 1324-1331]