N-terminal acetylation protects glucagon-like peptide GLP-1-(7-34)-amide from DPP-IV-mediated degradation retaining cAMP- and insulin-releasing capacity

Eur J Med Res. 2008 Feb 25;13(2):73-8.


Since its discovery glucagon-like peptide-1 (GLP-1) is investigated as a treatment for type II diabetes based on its major function as insulin secretagogue. A therapeutic use is, however, limited by its short biological half-life in the range of minutes, predominantly caused via degradation catalyzed by dipeptidyl peptidase IV (DPP-IV). Therefore, we aimed to design a GLP-1 analogue exhibiting resistance against DPP-IV-catalyzed inactivation while retaining its biological activity. By means of matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) we have studied the stability of the N-terminally blocked new analogue Ac-GLP-1-(7-34)-amide against DPP-IV and compared it with both unblocked GLP-1-(7-34)-amide and the major naturally occurring form GLP-1-(7-36)-amide. GLP-1-(7-36)-amide and the C-terminally two amino acid residues shorter GLP-1-(7-34)-amide rapidly generated peptide fragments truncated by the N-terminal dipeptide. In contrast, the N-terminal blocked Ac-GLP-1-(7-34)-amide was not degraded in the presence of DPP-IV over a period of at least two hours. Ac-GLP-1-(7-34)-amide induced a concentration-dependent increase of intracellular cAMP production and insulin release from rat insulinoma RIN-m5F cells to an extent comparable to that found for the N-terminally unblocked peptides GLP-1-(7-34)-amide and GLP-1-(7-36)-amide. Ac-GLP-1-(7-34)-amide may thus have the potential to act as a new long-acting GLP-1 analogue with significant resistance against DPP-IV and retained biological activity in vitro. Further research is required to investigate whether Ac-GLP-1-(7-34)-amide also exhibits its characteristics in animal models and humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Amides / chemistry*
  • Animals
  • Cells, Cultured
  • Cyclic AMP / metabolism*
  • Dipeptidyl Peptidase 4 / pharmacology*
  • Glucagon-Like Peptide 1 / analogs & derivatives
  • Glucagon-Like Peptide 1 / chemistry*
  • Glucagon-Like Peptide 1 / metabolism*
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulinoma / metabolism*
  • Insulinoma / pathology
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism
  • Rats
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization


  • Amides
  • Insulin
  • Peptide Fragments
  • acetyl-glucagon-like peptide 1 (7-34)-amide
  • Glucagon-Like Peptide 1
  • Cyclic AMP
  • Dipeptidyl Peptidase 4