title: In vivo and in vitro degradation of glucagon-like peptide-2 in humans.
abstract: Glucagon-like peptide-2 (GLP-2), an intestinal product of glucagon gene expression which induces intestinal growth in mice, has been proposed as a treatment for intestinal insufficiency. GLP-2 is metabolized extensively by dipeptidyl peptidase IV (DPP-IV) in rats, but less is known about its fate in humans. Therefore, GLP-2 metabolism was investigated in healthy volunteers after 1) a 500-Cal mixed meal (n = 6), 2) iv infusion of synthetic human GLP-2 (0.8 pmol/kg x min; n = 8), 3) a sc bolus injection (400 microg; n = 9), and 4) in vitro incubation in plasma and blood (1,000 pmol/L; n = 4). GLP-2 concentrations were determined by N-terminal RIA measuring only intact GLP-2, side-viewing RIA measuring intact and degraded forms [e.g. GLP-2-(3-33) arising from DPP-IV degradation], and high performance liquid chromatography (HPLC). Meal ingestion elevated plasma GLP-2 (intact, 16 +/- 3 to 73 +/- 10 pmol/L at 90 min), and HPLC revealed two immunoreactive components: intact GLP-2 (57 +/- 2%) and GLP-2-(3-33). GLP-2 infusion increased plasma levels [intact, 9 +/- 4 to 131 +/- 11 pmol/L; total, 23 +/- 7 to 350 +/- 18 pmol/L; the differences represent GLP-2-(3-33)]. The elimination t(1/2) values were 7.2 +/- 2 min (intact GLP-2) and 27.4 +/- 5.4 min [GLP-2-(3-33)], and MCRs were 6.8 +/- 0.6 and 1.9 +/- 0.3 mL/kg x min, respectively. Subcutaneous injection increased intact GLP-2 to maximally 1,493 +/- 250 pmol/L at 45 min, whereas total GLP-2 increased to 2,793 +/- 477 pmol/L at 90 min. At 60 min, plasma contained 69 +/- 1% intact GLP-2. In vitro the t(1/2) values were 8.0 +/- 1.5 h (plasma) and 3.3 +/- 0.3 h (blood). GLP-2-(3-33) was the only degradation product identified by HPLC, and a DPP-IV inhibitor abolished the degradation of GLP-2 in vitro. We conclude that GLP-2 is extensively degraded to GLP-2-(3-33) in humans, presumably by DPP-IV. Nevertheless, 69% remains intact 1 h after GLP-2 injection, supporting the possibility of sc use in patients with intestinal insufficiency.
authors.affiliation: Department of Medical Physiology, The Panum Institute, University of Copenhagen, Denmark.
authors.forename: B
authors.initials: B
authors.lastname: Hartmann
authors.forename: M B
authors.initials: MB
authors.lastname: Harr
authors.forename: P B
authors.initials: PB
authors.lastname: Jeppesen
authors.forename: M
authors.initials: M
authors.lastname: Wojdemann
authors.forename: C F
authors.initials: CF
authors.lastname: Deacon
authors.forename: P B
authors.initials: PB
authors.lastname: Mortensen
authors.forename: J J
authors.initials: JJ
authors.lastname: Holst
mesh_terms: D000328:Adult; D000818:Animals; D005260:Female; D053767:Glucagon-Like Peptide 2; D004763:Glucagon-Like Peptides; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D007700:Kinetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D010446:Peptide Fragments / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D010455:Peptides / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D019518:Postprandial Period; D051381:Rats; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism
chemical_list: D053767:Glucagon-Like Peptide 2; D010446:Peptide Fragments; D010455:Peptides; D011994:Recombinant Proteins; D004763:Glucagon-Like Peptides