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]