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Incretin cleavage by dipeptidyl peptidase 4 regulates post-prandial glucose and lipid handling.Mouse genetic studies revealed endothelial cell derived DPP4 as important for incretin cleavage.Elevated circulating DPP4 has a direct impact on cellular signaling and inflammation.Dipeptidyl peptidase 4 (DPP4) is a widely expressed, serine protease which regulates the bioactivity of many peptides through cleavage and inactivation including the incretin hormones, glucagon like peptide −1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP). Inhibitors of DPP4 are used therapeutically to treat patients with Type 2 Diabetes Mellitus (T2DM) as they potentiate incretin action to regulate islet hormone secretion and improve glycemia and post-prandial lipid excursions. The widespread clinical use of DPP4 inhibitors has increased interest in the molecular mechanisms by which these drugs mediate their beneficial effects. Traditionally, focus has remained on inhibiting the catalytic activity of DPP4 within the plasma compartment, however evidence is emerging on the importance of inactivation of membrane-bound DPP4 in selective tissue beds to potentiate local hormone gradients. Here we review the recent advances in identifying the cellular sources of both circulating and membrane-bound DPP4 important for cleavage of the incretin hormones and regulation of glucose and lipoprotein metabolism.