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Dipeptidyl peptidase (DPP)-IV inhibitors are a new approach to the treatment of type 2 diabetes. DPP-IV is a member of a family of serine peptidases that includes quiescent cell proline dipeptidase (QPP), DPP8, and DPP9; DPP-IV is a key regulator of incretin hormones, but the functions of other family members are unknown. To determine the importance of selective DPP-IV inhibition for the treatment of diabetes, we tested selective inhibitors of DPP-IV, DPP8/DPP9, or QPP in 2-week rat toxicity studies and in acute dog tolerability studies. In rats, the DPP8/9 inhibitor produced alopecia, thrombocytopenia, reticulocytopenia, enlarged spleen, multiorgan histopathological changes, and mortality. In dogs, the DPP8/9 inhibitor produced gastrointestinal toxicity. The QPP inhibitor produced reticulocytopenia in rats only, and no toxicities were noted in either species for the selective DPP-IV inhibitor. The DPP8/9 inhibitor was also shown to attenuate T-cell activation in human in vitro models; a selective DPP-IV inhibitor was inactive in these assays. Moreover, we found DPP-IV inhibitors that were previously reported to be active in models of immune function to be more potent inhibitors of DPP8/9. These results suggest that assessment of selectivity of potential clinical candidates may be important to an optimal safety profile for this new class of antihyperglycemic agents. Diabetes 54:2988-2994, 2005
Therapies that increase the circulating concentrations of insulin have proven beneficial in the treatment of type 2 diabetes. Dipeptidyl peptidase (DPP)-IV inhibitors are a promising new approach to type 2 diabetes that function, at least in part, as indirect stimulators of insulin secretion (1). Clinical proof of concept for the efficacy of DPP-IV inhibitors has been provided by LAF237 (2,3). Additional proof of concept has been obtained in studies with DPP-IV-deficient mice, which are healthy, fertile, and have improved metabolic function (4,5).
The efficacy of DPP-IV inhibitors is mediated primarily via stabilization of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide, which have clearly established roles in glucose-dependent insulin secretion (6). Subchronic (6 weeks) continuous infusion of GLP-1 resulted in profound and significant decreases in fasting plasma glucose and HbA^sub 1c^ (1.3%) (7). GLP-1 is rapidly hydrolyzed (t^sub 1/2^ = ~1 min) in vivo to produce an inactive product, GLP-1 [9-36] amide (8), and several lines of evidence indicate that DPP-IV, a proline-specific serine...