Degradation of Glucagon-Like peptide-1 by Human Plasma in Vitro Yields an N-terminally Truncated Peptide That Is a Major Endogenous Metabolite in Vivo

J Clin Endocrinol Metab. 1995 Mar;80(3):952-7. doi: 10.1210/jcem.80.3.7883856.

Abstract

The metabolism of glucagon-like peptide-1 (GLP-1) has not been studied in detail, but it is known to be rapidly cleared from the circulation. Measurement by RIA is hampered by the fact that most antisera are side-viewing or C-terminally directed, and recognize both intact GLP-1 and biologically inactive. N-terminally truncated fragments. Using high pressure liquid chromatography in combination with RIAs, methodology allowing specific determination of both intact GLP-1 and its metabolites was developed. Human plasma was shown to degrade GLP-1-(7-36)amide, forming an N-terminally truncated peptide with a t1/2 of 20.4 +/- 1.4 min at 37 C (n = 6). This was unaffected by EDTA or aprotinin. Inhibitors of dipeptidyl peptidase-IV or low temperature (4 C) completely prevented formation of the metabolite, which was confirmed to be GLP-1-(9-36)amide by mass spectrometry and sequence analysis. High pressure liquid chromatography revealed the concentration of GLP-1-(9-36)amide to be 53.5 +/- 13.7% of the concentration of endogenous intact GLP-1 in the fasted state, which increased to 130.8 +/- 10.0% (P < 0.01; n = 6) 1 h postprandially. Metabolism at the C-terminus was not observed. This study suggests that dipeptidyl peptidase-IV is the primary mechanism for GLP-1 degradation in human plasma in vitro and may have a role in inactivating the peptide in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromatography, High Pressure Liquid
  • Female
  • Glucagon / blood
  • Glucagon / metabolism*
  • Glucagon-Like Peptide 1
  • Humans
  • Male
  • Peptide Fragments / blood
  • Peptide Fragments / metabolism*
  • Protein Precursors / blood
  • Protein Precursors / metabolism*

Substances

  • Peptide Fragments
  • Protein Precursors
  • Glucagon-Like Peptide 1
  • Glucagon