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

Excerpt

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]. …