What mediates the benefits associated with dipeptidyl peptidase-IV inhibition?

Abstract

Inhibitors of the enzyme dipeptidyl peptidase-IV (DPP-IV) are a new class of agents for the treatment of type 2 diabetes [1]. DPP-IV is responsible for the rapid inactivation of glucagon-like peptide-1 (GLP-1), reducing its active half-life to only 1–2 min. GLP-1 is an incretin hormone that is released from the gut when food is ingested to augment glucose-stimulated insulin secretion [2]. It exhibits multiple actions that are beneficial for the treatment of type 2 diabetes, including glucose-dependent stimulation of insulin secretion, inhibition of glucagon secretion, delaying gastric emptying, and induction of satiety. In addition, it has the potential to increase beta cell mass by stimulating the differentiation of precursor cells into beta cells and by inhibiting beta cell apoptosis [2]. The beneficial effects of GLP-1 were shown as early as 1992 and have been supported by numerous studies, one of which investigated the effects of a continuous 6-week subcutaneous infusion [3, 4]. GLP-1 therefore offers a novel approach to the treatment of type 2 diabetes, but its positive effects are counterbalanced by the need for continuous infusion. This limitation may be overcome by the development of GLP-1 receptor agonists (GLP-1 mimetics) with either low affinity or no affinity for DPP-IV. The discovery that DPP-IV can cleave GLP-1 in plasma [5], whether exogenously administered or endogenously secreted [6, 7], has opened the way for an alternative strategy for the treatment of type 2 diabetes— the development of inhibitors of DPP-IV [8]. Although the rationale for the use of DPP-IV inhibitors is based upon their prolonging the actions of GLP-1, they also have other beneficial effects. DPP-IV inhibition blocks the inactivation of the other major incretin hormone, gastric inhibitory peptide (GIP). DPP-IV inhibitors therefore enhance concentrations of the active forms of both incretin hormones precisely when they are most needed (i.e. following meal ingestion), resulting in improved postprandial glucose control. Since the actions of both GLP-1 and GIP are glucose dependent, DPP-IV inhibition has the additional advantage that it carries a minimal risk of hypoglycaemia. Treatment with GLP-1 also lowers fasting glucose levels. Further support for this approach to therapy comes from the observations that glucose tolerance is improved in animals in which the enzyme has been genetically deleted [9] and in animals treated with DPP-IV inhibitors [10]. Clinical studies of type 2 diabetes show improved metabolic control, increased insulin secretion, reduced glucagon secretion, and favourable tolerability and safety during a treatment period of up to 1 year [11–13]. For example, the addition of a DPPIV inhibitor to metformin resulted in a reduction in HbA1c of 1.1% relative to metformin plus placebo by the end of 1 year [13] (Fig. 1). DPP-IV is a widespread enzyme with the potential to cleave a large number of bioactive peptides other than GLP1 and GIP [14]. The requisite for cleavage is that an alanine or a proline must be present as the second amino acid from the N-terminal end, in which case the two N-terminal amino acids are cleaved from the rest of the peptide. When this cleavage results in a loss of activity, as with GLP-1 and GIP, DPP-IVacts as an inactivation enzyme. However, it is possible that the effects of DPP-IV inhibition in diabetes are mediated by the inhibition of bioactive peptides other than GLP-1. One puzzling finding might support this: in patients with type 2 diabetes, concentrations of active GLP-1 after meal ingestion are doubled by DPP-IV inhibition (compared with placebo), and glucose control improves [13]. In contrast, when similar increases in GLP-1 levels are proB. Ahren (*) Department of Medicine, Lund University, Lund, Sweden e-mail: Bo.Ahren@med.lu.se Tel.: +46-46-2220758 Fax: +46-46-2220757