DPP4 in Diabetes

Abstract

Dipeptidyl-peptidase 4 (DPP4) is a glycoprotein of 110 kDa, which is ubiquitously expressed on the surface of a variety of cells. This exopeptidase selectively cleaves N-terminal dipeptides from a variety of substrates, including cytokines, growth factors, neuropeptides, and the incretin hormones. Expression of DPP4 is substantially dysregulated in a variety of disease states including inflammation, cancer, obesity, and diabetes. Since the incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (GIP), are major regulators of post-prandial insulin secretion, inhibition of DPP4 by the gliptin family of drugs has gained considerable interest for the therapy of type 2 diabetic patients. In this review, we summarize the current knowledge on the DPP4-incretin axis and evaluate most recent findings on DPP4 inhibitors. Furthermore, DPP4 as a type II transmembrane protein is also known to be cleaved from the cell membrane involving different metalloproteases in a cell-type-specific manner. Circulating, soluble DPP4 has been identified as a new adipokine, which exerts both para- and endocrine effects. Recently, a novel receptor for soluble DPP4 has been identified, and data are accumulating that the adipokine-related effects of DPP4 may play an important role in the pathogenesis of cardiovascular disease. Importantly, circulating DPP4 is augmented in obese and type 2 diabetic subjects, and it may represent a molecular link between obesity and vascular dysfunction. A critical evaluation of the impact of circulating DPP4 is presented, and the potential role of DPP4 inhibition at this level is also discussed.

Keywords: CD26/DPP4; DPP4 inhibitors/gliptins; incretins; multifunctional enzyme; soluble DPP4; type 2 diabetes mellitus.

Figure 1

Domain structure of DPP4 [adapted from Ref. (2)]. Schematic representation of the membrane-bound DPP4 monomer. The extent of the circulating and soluble form of DPP4 is illustrated on the left in blue. The shedding of DPP4 from the membrane by indicated matrix metalloproteinases is shown by a scissor symbol in red. The vertical black bar on the right represents the primary structure with the delineation of the different regions. In green are interactions collected, which occur in the indicated region of the DPP4 structure. MMP, matrix metalloproteinase; M6P/IGFII, mannose-6 phosphate/insulin-like growth factor 2.

Figure 2

Schematic overview of the impact of soluble DPP4 and DPP4 inhibitors on T2DM-relevant organs/tissues. In the upper panel, direct effects of soluble DPP4 (in red) on different organs/tissues are presented (gray boxes). The lower panel shows known effects of DPP4 inhibitors (in green) in these particular organs/tissues (gray boxes). SMC, smooth muscle cells.