In vivo and in vitro degradation of peptide YY_3–36 to inactive peptide YY_3–34 in humans

Abstract

-Peptide YY (PYY) is a 36-amino-acid peptide released from enteroendocrine cells upon food intake. The NH 2 terminally truncated metabolite, PYY3-36, exerts anorexic effects and has received considerable attention as a possible antiobesity drug target. The kinetics and degradation products of PYY metabolism are not well described. A related peptide, neuropeptide Y, may be degraded from the COOH terminus, and in vivo studies in pigs revealed significant COOH-terminal degradation of PYY. We therefore investigated PYY metabolism in vitro after incubation in human blood and plasma and in vivo after infusion of PYY 1-36 and PYY3-36 in eight young, healthy men. A metabolite, corresponding to PYY 3-34, was formed after incubation in plasma and blood and during the infusion of PYY. PYY 3-34 exhibited no agonistic or antagonistic effects on the Y2 receptor. PYY 1-36 infused with and without coadministration of sitagliptin was eliminated with half-lives of 10.1 Ϯ 0.5 and 9.4 Ϯ 0.8 min (means Ϯ SE) and metabolic clearance rates of 15.7 Ϯ 1.5 and 14.1 Ϯ 1.1 ml·kg Ϫ1 ·min Ϫ1 after infusion, whereas PYY 3-36 was eliminated with a significantly longer half-life of 14.9 Ϯ 1.3 min and a metabolic clearance rate of 9.4 Ϯ 0.6 ml·kg Ϫ1 ·min Ϫ1 . We conclude that, upon intravenous infusion in healthy men, PYY is inactivated by cleavage of the two COOHterminal amino acids. In healthy men, PYY 3-36 has a longer half-life than PYY 1-36. peptide YY; kinetics; degradation PEPTIDE YY (PYY) is a gastrointestinal peptide hormone, released into the circulation in response to food intake (3,4,8,18), belonging to the pancreatic polypeptide family together with neuropeptide Y (NPY) and pancreatic polypeptide. These are all 36-amino-acid peptides characterized by a high content of tyrosine, proline, and arginine and a hairpin structure, the so-called " 21).PYY is synthesized and released from endocrine L-cells in the intestinal mucosa, often together with proglugacon-derived peptides, namely glucagon-like peptide-1 (GLP-1), GLP-2, oxyntomodulin, and glicentin. PYY immunoreactive cells are found primarily in ileum and colon with increasing density distally (4).PYY is present in plasma in two major molecular forms, the 36-amino-acid form, PYY 1-36 , and the 34-amino-acid NH 2 -terminally truncated form, PYY 3-36 , which is formed by cleavage of the two NH 2 -terminal amino acids by the enzyme dipeptidyl peptidase-4 (DPP-4) (28). DPP-4 is present in both a soluble form and as a transmembrane protein in endothelial, epithelial, and lymphoid tissue. DPP-4 cleaves and inactivates, e.g., glucose-dependent insulinotropic polypeptide and GLP-1 with short plasma half-lives of 5 and 1-2 min, respectively (15,23,36).Anorexigenic effects of PYY 3-36 have been demonstrated in several studies with intravenous administration of PYY 3-36 (6, 16, 32, 34), whereas infusions of PYY 1-36 have no effect on food intake (34), suggesting that the cleavage of PYY 1-36 to PYY 3-36 is not as complete and rapid as for GLP-1 (34). The half-life of PYY 1-36 has been deter...

Development and validation of an LC-MS/MS method for detection and quantification of in vivo derived metabolites of [Pyr1]apelin-13 in humans

“…Interestingly, like [Pyr 1 ]apelin-13, arginine vasopressin was also proposed to be cleaved in vivo from both the C-and N-termini, with carboxypeptidase and post-proline enzymes cleaving the C-terminus of arginine vasopressin, while aminopeptidases cleaved the N-terminal region [33][34][35] . In contrast, other in vivo studies of this nature identified only a single terminus cleavage of Peptide YY 36 , growth hormone-releasing hormone 37 , liraglutide, a glucagon-like peptide-1 (GLP-1) analogue 38 and big endothelin-1 39 .…”

On the relationship between glucose absorption and glucose‐stimulated secretion of GLP ‐1, neurotensin, and PYY from different intestinal segments in the rat

“…); (Torang et al. )). For the NT assay, the detection limit is 2 pmol/L with an intraassay coefficient of variation of 9% and the PYY assay had comparable characteristics.…”

Chenodeoxycholic acid stimulates glucagon‐like peptide‐1 secretion in patients after Roux‐en‐Y gastric bypass

“…Total PYY was measured by an in‐house RIA using a monoclonal antibody MAB8500 as described elsewhere (Toräng et al. ).…”