Abstract
Dipeptidyl peptidase-4 (DPP-4), also known as the T-cell antigen CD26, is a multi-functional protein which, besides its catalytic activity, also functions as a binding protein and a ligand for a variety of extracellular molecules. It is an integral membrane protein expressed on cells throughout the body, but is also shed from the membrane and circulates as a soluble protein in the plasma. A large number of bioactive molecules can be cleaved by DPP-4 in vitro, but only a few of these have been demonstrated to be physiological substrates. One of these is the incretin hormone, glucagon-like peptide-1 (GLP-1), which plays an important role in the maintenance of normal glucose homeostasis, and DPP-4 has been shown to be the key enzyme regulating its biological activity. This pathway has been targeted pharmacologically through the development of DPP-4 inhibitors, and these are now a successful class of anti-hyperglycaemic agents used to treat type 2 diabetes (T2DM). DPP-4 may additionally influence metabolic control via its proteolytic effect on other regulatory peptides, but it has also been reported to affect insulin sensitivity, potentially mediated through its non-enzymatic interactions with other membrane proteins. Given that altered expression and activity of DPP-4 are associated with increasing body mass index and hyperglycaemia, DPP-4 has been proposed to play a role in linking obesity and the pathogenesis of T2DM by functioning as a local mediator of inflammation and insulin resistance in adipose and hepatic tissue. As well as these broader systemic effects, it has also been suggested that DPP-4 may be able to modulate β-cell function as part of a paracrine system involving GLP-1 produced locally within the pancreatic islets. However, while it is evident that DPP-4 has the potential to influence glycaemic control, its overall significance for the normal physiological regulation of glucose homeostasis in humans and its role in the pathogenesis of metabolic disease remain to be established.
Highlights
Dipeptidyl peptidase-4 (DPP-4; EC 3.4.14.5) is a member of the prolyl oligopeptidase family of related proteins, which, besides prolyl oligopeptidase (a.k.a. prolyl endopeptidase), contains a number of exopeptidases, including quiescent cell proline dipeptidase
This study investigated the expression of dipeptidyl peptidase (DPP)-4 and found it to be present on the vascular endothelium, including the local capillaries in the lamina propria adjacent to the glucagon-like peptide-1 (GLP-1) producing L-cells, providing an explanation for the rapid degradation of the peptide once it had been released
The involvement of DPP-4 in metabolism of endogenous Stromal cell-derived factor-1α (SDF-1α) is compatible with the finding that the truncated metabolite, SDF-1α 3-67, was present in wild-type mice, but not in animals lacking DPP-4 [62], with this observation being extended in subsequent studies in mice and Rhesus monkeys [63] and in patients with type 2 diabetes mellitus (T2DM) [64] showing that levels of SDF-1α 367 were reduced while those of the intact 1-67 form increased concomitantly when DPP-4 activity was inhibited
Summary
Dipeptidyl peptidase-4 (DPP-4; EC 3.4.14.5) is a member of the prolyl oligopeptidase family of related proteins, which, besides prolyl oligopeptidase (a.k.a. prolyl endopeptidase), contains a number of exopeptidases, including quiescent cell proline dipeptidase As in the shorter-term studies, DPP-4 inhibition was well-tolerated with no increased risk of hypoglycaemia, despite the improvement in glycaemic control, and the overall adverse event profile was similar in both arms of the study These key studies clearly provided clinical proofof-concept that blocking the catalytic activity of DPP-4 could be a viable approach to treat T2DM, whilst at the same time helped to allay concern over whether the metabolism of any other potential DPP-4 substrates might be affected to cause unwanted off-target effects. The involvement of DPP-4 in metabolism of endogenous SDF-1α is compatible with the finding that the truncated metabolite, SDF-1α 3-67, was present in wild-type mice, but not in animals lacking DPP-4 [62], with this observation being extended in subsequent studies in mice and Rhesus monkeys [63] and in patients with T2DM [64] showing that levels of SDF-1α 367 were reduced while those of the intact 1-67 form increased concomitantly when DPP-4 activity was inhibited. The preclinical studies cited above point toward potential metabolic effects of SDF-1α, it is unknown whether there are any physiological or pharmacological consequences of DPP-4-mediated cleavage of SDF-1α for metabolic control in humans
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