Dipeptidyl Peptidase IV Inhibition for the Treatment of Type 2 Diabetes

Abstract

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

Reversible Inactivation of Human Dipeptidyl Peptidases 8 and 9 by Oxidation

“…DP8 expression upregulation by activated T cells and T cell proliferation suppression by DP8/9 inhibitors suggests that such substrates and thus a role of DP8/9 may be in immune cells [32,37]. The present study showed that thiol groups of DP8 and DP9 are targets of oxidation -reduction processes that impact upon enzyme activity.…”

Inhibition of CD26/Dipeptidyl Peptidase IV Enhances CCL11/Eotaxin-Mediated Recruitment of Eosinophils In Vivo

“…Although the DPPIV inhibitor Ile-thia has been shown to also inhibit the intracellularly located DPPIV-related dipeptidyl peptidases DP8 and DP9, the results obtained from the DPPIV neg rats and the in vitro experiments with CCL11 and serum give strong evidence that the observed effects virtually depend on the activity of DPPIV (36).…”

Phenotyping of congenic dipeptidyl peptidase 4 (DP4) deficient Dark Agouti (DA) rats suggests involvement of DP4 in neuro-, endocrine, and immune functions

“…Similar findings were observed in female animals w(-/-) 1.88"0.1 mU/mL; (q/q) 36.1"1.2 mU/mL; (q/-) 15.3"0.9 mU/mLx. In support of DP4 being the key regulator in glucose homeostasis, testing glucose tolerance in the OGTT revealed a significantly improved response towards glucose load in DP4 deficient rats wF(2,20)s10.04, ps0.001; Figure 1Bx, being comparable to pharmacologically induced DP4 deficiency in mice (29,30). Interestingly, heterozygous animals exhibited an intermediate phenotype, clearly illustrating an association between ''gene dosis'', DP4 activity, and glucose tolerance.…”