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In Vivo and in Vitro Degradation of Glucagon-Like Peptide-2 in Humans*.
Hartmann, Bolette; Harr, Mette B; Jeppesen, Palle B; Wojdemann, Morten; Deacon, Carolyn F; Mortensen, Per B; Holst, Jens J
[Article] Journal of Clinical Endocrinology & Metabolism. 85(8):2884-2888, August 2000.

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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[middle dot]min; n = 8), 3) a sc bolus injection (400 [mu]g; n = 9), and 4) in vitro incubation in plasma and blood (1000 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 t1/2 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[middle dot]min, respectively. Subcutaneous injection increased intact GLP-2 to maximally 1493 /- 250 pmol/L at 45 min, whereas total GLP-2 increased to 2793 /- 477 pmol/L at 90 min. At 60 min, plasma contained 69 /- 1% intact GLP-2. In vitro the t1/2 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.