Our opponents in this debate, Nauck and El-Ouaghlidi, have challenged the standard view that the therapeutic actions of the dipeptidyl peptidase-IV (DPP-IV) inhibitors are mediated by glucagon-like peptide-1 (GLP-1)[1]. Based on the findings that exogenously administered GLP-1 is rapidly and extensively degraded by DPP-IV [2], and that this degradation appears to be mediated by DPP-IV [3], it was proposed that DPP-IV inhibitors could enhance the survival of intact, biologically active GLP-1 and thus be of use in the treatment of type 2 diabetes mellitus [2, 4]. Although the kinetic studies performed by Mentlein et al. clearly demonstrated that DPP-IV may have substrates in addition to GLP-1 [5, 6], the effect of this enzyme on GLP-1 was considered to be of particular importance because:(1) GLP-1 is extremely susceptible to rapid degradation by DPP-IV, as compared with the majority of other substrates;(2) DPP-IV degradation is the primary route of GLP-1 inactivation;(3) GLP-1 is perhaps the most potent and efficacious insulinotropic hormone in the body [7], whereas gastric inhibitory peptide (GIP), the other major incretin hormone, has no insulinotropic effects in patients with type 2 diabetes [8]; and (4) DPP-IV inhibitors have no metabolic effect in mice with a targeted deletion of the GLP-1 and GIP receptor genes [9].

The authors of the previous article have listed five arguments that have caused them to doubt that GLP-1 is the only, or at least the major, mediator of the remarkable hypoglycaemic effects of DPP-IV inhibitors observed in clinical studies [10–12]. We would certainly agree that there are other potential substrates for DPP-IV whose extended survival might contribute to the therapeutic effects of these inhibitors; nonetheless, we believe that the protection of GLP-1 against degradation is the major mechanism involved. In the remainder of this paper, we shall respond to each of the five arguments in turn.