The Nonglycemic Actions of Dipeptidyl Peptidase-4 Inhibitors

Abstract

A cell surface serine protease, dipeptidyl peptidase 4 (DPP-4), cleaves dipeptide from peptides containing proline or alanine in the N-terminal penultimate position. Two important incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), enhance meal-stimulated insulin secretion from pancreatic β-cells, but are inactivated by DPP-4. Diabetes and hyperglycemia increase the DPP-4 protein level and enzymatic activity in blood and tissues. In addition, multiple other functions of DPP-4 suggest that DPP-4 inhibitor, a new class of antidiabetic agents, may have pleiotropic effects. Studies have shown that DPP-4 itself is involved in the inflammatory signaling pathway, the stimulation of vascular smooth cell proliferation, and the stimulation of oxidative stress in various cells. DPP-4 inhibitor ameliorates these pathophysiologic processes and has been shown to have cardiovascular protective effects in both in vitro and in vivo experiments. However, in recent randomized clinical trials, DPP-4 inhibitor therapy in high risk patients with type 2 diabetes did not show cardiovascular protective effects. Some concerns on the actions of DPP-4 inhibitor include sympathetic activation and neuropeptide Y-mediated vascular responses. Further studies are required to fully characterize the cardiovascular effects of DPP-4 inhibitor.

Ineffectiveness of saxagliptin as a neuroprotective drug in 6-OHDA-lesioned rats

“…The substrates reported include hormones, chemokines and several neuropeptides, such as substance P, neuropeptide Y, peptide YY, endomorphin‐1 and endomorphin‐2. Thus, the actions of these drugs might increase the levels of a variety of active peptides in vivo . On the other hand, DPP‐4 inhibitors also interact with other dipeptidyl peptidases including DPP‐8 and DPP‐9 .…”

Regulation of Chemokine Activity – A Focus on the Role of Dipeptidyl Peptidase IV/CD26

“…Membrane-bound CD26 contains a transmembrane domain that is located 28 residues from the NH 2 -terminus and is a leukocyte surface marker (176, 181, 182). The protein shows catalytic proteolytic activity only as a dimer and can be found on the surface of T and B cells, NK cells, some types of macrophages, and hematopoietic stem and progenitor cells.…”

Past and current perspective on new therapeutic targets for Type-II diabetes

“…The active forms of GLP and GIP increase the insulin secretion and regulate the glucose homeostasis. Upon release, GLP and GIP are immediately inactivated by dipeptidyl peptidase-4 (DP4) hence they have very short half-life 69. Therefore, the discovery of DP4 inhibitors is a promising approach toward the development of novel anti-diabetic drugs.…”