Porcine glucagon-like peptide-2: structure, signaling, metabolism and effects.
Mass spectrometry of HPLC-purified porcine glucagon-like peptide-2 (pGLP-2)(1) revealed a 35 amino acid sequence with C-terminal Ser and Leu, in contrast to the 33 amino acids of human, cow, rat and mouse GLP-2. Synthetic pGLP-2 stimulated cAMP-production in COS-7 cells expressing human GLP-2 (hGLP-2) receptor with the same potency and efficacy as hGLP-2. In anesthetized pigs (n=9) given intravenous pGLP-2 infusions, the half life (t1/2) of intact pGLP-2 (8.4+/-0.9 min) was shorter (p<0.01) than that of the primary metabolite pGLP-2 (3-35) (34.0+/-5.2 min), generated by dipeptidyl peptidase-4 (DPP-4) cleavage. Adding the DPP-4 inhibitor valine-pyrrolidide prolonged t1/2 of intact pGLP-2 (p<0.05). The metabolic clearance rate (MCR) of intact pGLP-2 (23.9+/-3.82 mL/(kg x min)) was greater (p<0.0001) than that of pGLP-2 (3-35) (6.36+/-1.45 mL/(kg x min)) and larger than the previously reported MCR of hGLP-2 in pig. The MCR of intact pGLP-2 was reduced by valine-pyrrolidide (p<0.05), but was still greater than that of intact hGLP-2 previously reported. In the isolated perfused porcine pancreas, pGLP-2 stimulated glucagon release (p<0.05), but had no effect on insulin or somatostatin release. Exocrine secretion was unaffected and there was no apparent vasoactive effect. In mice (n=8), both subcutaneous hGLP-2 and pGLP-2 given twice daily for 10 days, significantly and equally increased small intestinal weight, length and cross-sectional area of proximal ileum. In conclusion, pGLP-2 and hGLP-2 have similar effects in vivo and in vitro in spite of the structural differences. However, pGLP-2 is cleared more rapidly in pigs than hGLP-2.
Pedersen
Nis B
NB
Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Hjollund
Karina R
KR
Johnsen
Anders H
AH
Orskov
Cathrine
C
Rosenkilde
Mette M
MM
Hartmann
Bolette
B
Holst
Jens J
JJ
D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D053767:Glucagon-Like Peptide 2 / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D051381:Rats; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology; D013552:Swine
D053767:Glucagon-Like Peptide 2