Therapeutic Potential Of Dppiv Inhibition

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With its unique substrate specificity and localization as an ectoenzyme at the plasma membrane, DPP-IV plays an important role in initiating N-terminal degradation of a number of neuropeptides, peptide hormones and chemokines with N-terminal Xaa-Pro and Xaa-Ala. However, most studies reporting cleavage of synthetic peptide substrates are under in vitro conditions, making predictions of a physiological role for DPP-IV in the control of biological activity of most substrates speculative. A number of recent reviews support divergent roles for DPP-IV in the modulation of biological activity of a variety of substrates (9-11,43). Indeed, DPP-IV-mediated cleavage of peptide hormones has been shown to lead to total inactivation, partial inactivation, altered receptor affinity, or no alteration of biological function, depending on the substrate being investigated. This potential for synergistic and antagonistic interplay between the processed substrates, along with the difficulties associated with detection and quantification of small DPP-IV-processed substrates, has hampered efforts to establish a precise role for DPP-IV in any given process.

Attempts to determine the therapeutic potential of inhibiting DPP-IV activity in vivo have been further complicated by a multiplicity of enzymes reported to exhibit DPP-IV-like activity; including quiescent cell proline dipeptidase (QPP), dipeptidyl peptidase-ivp (DPP-IVP), dipeptidyl peptidase-8 (DPP-8), fibroblast-activation protein (FAP or CD8) and dipeptidyl peptidase II (DPP-II) (44-51). DPP-IV deficient or knockout animal models have been valuable in establishing the role for DPP-IV in individual pathways. Both a DPP-IV-deficient rat sub-strain (DPP-IV negative Fischer 344 rats) and a DPP-IV knockout mouse are fertile and healthy (52,53). Biological function and turnover of four Xaa-Ala peptide substrates have been investigated in these models, including two of the most potent insulinotropic agents presently known, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), an intestinal growth factor, glucagon-like peptide-2 (GLP-2), and growth-releasing hormone (GRH). Recent literature on the potential therapeutic value of DPP-IV inhibitors has focused mainly on GLP-1 and GIP as the rationale for use of DPP-IV inhibitors in type 2 diabetes.

Type 2 diabetes - GLP-1 stimulates glucose-dependent insulin secretion, inhibits glucagon release, slows gastric emptying, promotes growth and differentiation of (3-cells, and stimulates insulin gene expression and biosynthesis (54-58). Numerous studies support a rate-limiting function for DPP-IV in inactivating GLP-1 in vivo

(59-63). More importantly, the contribution of DPP-IV in the regulation of glucose levels through GLP-1 inactivation has recently been confirmed by the examination of GLP-1 effects in both the DPP-IV knockout mouse and the hyperglycemic, GLP-1 receptor knockout mouse (64). Due to these multiple benefits of GLP-1 augmentation, DPP-IV inhibition has been recognized as a mechanistic approach of potential value to the treatment of type 2 diabetes (8). Studies with exogenous GLP-1 and DPP-IV resistant GLP-1 analogs have shown that normalized glucose levels are achieved in type 2 diabetics by increasing circulating levels of active GLP-1 by 3- to 4-fold (65-68). Val-pyrrolidide, a structurally related DPP-IV inhibitor (K = 0.4 pM), completely inhibited the NH2-terminal degradation of GLP-1 and significantly augmented the insulin response to glucose in GLP-1 infused pigs and mice (69,70). A competitive, reversible DPP-IV inhibitor, lle-thiazolidide (Kj = 0.13 pM), prevented the degradation of infused GLP-1 which resulted in augmented insulin responses to glucose and enhanced glucose clearance in both normal and obese rat models (71,72). A potent and selective DPP-IV inhibitor (K = 11 nM), 7 normalized glucose excursion in an obese fa/fa rat model and augmented active GLP-1 levels 3-fold in humans (73-75). Studies with Val-pyrrolidide, DPP-IV-knockout mice and glucose intolerant GIP-knockout mice confirmed DPP-IV's role in GIP inactivation and provide another mechanism for the control of glucose-dependent insulin secretion via DPP-IV inhibition (64,76).

Growth factors - In vitro and in vivo studies in mice, rats, and humans have shown that DPP-IV is the primary inactivation pathway for the intestinal growth factor, GLP-2 (77-79). Approaches that prevent GLP-2 degradation, such as the use of DPP-IV resistant GLP-2 analogs , DPP-IV deficient rats, or DPP-IV inhibitors have been more effective at promoting small intestinal mucosa growth than natural GLP-2 in normal rats alone (8,78). A DPP-IV inhibitor may therefore be considered therapeutic in conjunction with GLP-2 administration to encourage mucosal regeneration in patients with intestinal disease (66,80). However, the importance of DPP-IV inhibition to preserve intact GLP-2, at least in man, is questionable due to the recently reported low inactivation rate (ti/2 > 1h) (79).

In vitro and in vivo studies in rat, pig, and cattle have established DPP-IV mediated proteolysis as a major route of GRH degradation and inactivation (81-84). Increases in hormone activity have been shown in vivo in both DPP-IV resistant GRH analogs in cattle and DPP-IV inhibitors co-administered with GRH in rats (82,84). In situations of sub-normal development or dwarfism, DPP-IV inhibition may potentially reduce the amount or frequency of GRH dosing.

Other functions of DPP-IV - Known as CD26 in the immunology field, DPP-IV is a well-established marker of T-lymphocyte activation (14,17,85). DPP-IV is present on the surface of activated T-cells where it participates in T-cell modulation through direct physical interactions with CD45 and possibly other T-cell surface molecules. With DPP-IV mutants which are devoid of the catalytic site, it has been demonstrated that DPP-IV enzymatic activity is not required for normal T-cell function (14).

Human DPP-IV also serves as a membrane-anchoring protein for ecto-adenosine deaminase (ADA), which has been postulated to detoxify extracellular adenosine or 2'-deoxyadenosine and to modulate the co-stimulatory function of CD26 on T-lymphocytes (86,87). The binding of ADA to DPP-IV does not require DPP-IV enzymatic activity and is mediated at least in part by residues in the non-catalytic cysteine-rich domain of DPP-IV (88,89).

Other observations - Alterations of DPP-IV expression or serum activity occur in several clinical and experimental cases of altered immune function (90). Serum DPP-IV activities are significantly increased in cases of allograft rejection, anorexia nervosa and periodontal disease, but are decreased in systemic lupus, rheumatoid arthritis, pregnancy, depression, and schizophrenia (91-98). HIV-infected patients have normal serum DPP-IV activity but with a decreased number of DPP-IV-positive lymphocytes (99). DPP-IV has been employed as a cell surface marker in the histological evaluation of a wide range of tumor types. Tumors have been described with either increased or decreased expression of CD26/DPP-IV, and this divergent expression has been associated with both an increased and decreased aggressiveness of growth of the tumors in question. Tumors with high cell-surface DPP-IV activity/expression include B chronic lymphocytic leukemia, basal cell carcinoma, T cell lymphoma, thyroid carcinoma, breast cancer, hepatocellular carcinoma, and lung tumors, while tumors with reduced or absent DPP-IV activity/CD26 expression include squamous cell carcinoma and melanoma (88,100108). Presently, it is unclear whether changes in DPP-IV expression contribute to, or are a reflection of, the transformed status of the cells. Causal relationships between DPP-IV serum levels and disease states have yet to be determined.

Under controlled situations where proline is a major dietary amino acid, DPP-IV has been shown to play an important role in intestinal proline absorption and recovery of proline through re-absorption from the renal proximal tubuli (109). With a normal, non-proline rich reference diet administered over four weeks to both normal and DPP-IV deficient (DDR) Fischer 344 rats, no difference in the growth rate of either group was observed (109). However, significant weight loss was observed for the DDR rats compared to control when fed a diet that contained 20% of proline-rich gliadin as the sole source of protein over the same time period. Since proline is not a major component of dietary protein and is readily synthesized from L-glutamate, the potential clinical relevance of these differences is unclear.

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