Control of prandial plasma concentrations of substrates, particularly glucose, is aided by incretins. Incretins are hormones released by the digestive tract in response to ingested nutrients [1]. The role of incretins is to sensitize beta cells to stimulation by glucose, leading to an accelerated and augmented insulin response to absorbed glucose. The two most prominent incretins are gastric inhibitory polypeptide/glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The first is released by K cells in the duodenum and jejunum [2] whereas GLP-1 is produced in L cells in the distal small intestine and in the colon [3]. Both GLP-1 and GIP augment glucose-stimulated insulin secretion [4,5] and increase intracellular cAMP concentrations in beta cells [6]. Although some controversy exists regarding the relative importance of each of these incretins, both hormones have strong priming effects on the beta cells [7]. Several studies have shown that Diabetologia (1999) Abstract 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