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∙min)) was greater (p < 0.0001) than that of pGLP-2 (3–35) (6.36 ± 1.45 mL/(kg∙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.