Metabolic stability, receptor binding, cAMP generation, insulin secretion and antihyperglycaemic activity of novel N-terminal Glu9-substituted analogues of glucagon-like peptide-1

Brian D. Green*, Victor A. Gault, Nigel Irwin, Mark H. Mooney, Clifford J. Bailey, Patrick Harriott, Brett Greer, Peter R. Flatt, Finbarr P M O'Harte

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Glucagon-like peptide-1(7-36)amide (GLP-1) is an incretin hormone with therapeutic potential for type 2 diabetes. Rapid removal of the N-terminal dipeptide, His7-Ala8, by the ubiquitous enzyme dipeptidyl peptidase IV (DPP IV) curtails the biological activity of GLP-1. Chemical modifications or substitutions of GLP-1 at His7 or Ala8 improve resistance to DPP-IV action, but this often reduces potency. Little attention has focused on the metabolic stability and functional activity of GLP-1 analogues with amino acid substitution at Glu9, adjacent to the DPP IV cleavage site. We generated three novel Glu9-substituted GLP-1 analogues, (Pro9)GLP-1, (Phe9)GLP-1 and (Tyr9)GLP-1 and show for the first time that Glu9 of GLP-1 is important in DPP IV degradation, since replacing this amino acid, particularly with proline, substantially reduced susceptibility to degradation. All three novel GLP-1 analogues showed similar or slightly enhanced insulinotropic activity compared with native GLP-1 despite a moderate 4-10-fold reduction in receptor binding and cAMP generation. In addition, (Pro9)GLP-1 showed significant ability to moderate the plasma glucose excursion and increase circulating insulin concentrations in severely insulin resistant obese diabetic (ob/ob) mice. These observations indicate the importance of Glu9 for the biological activity of GLP-1 and susceptibility to DPP IV-mediated degradation.

Original languageEnglish
Pages (from-to)1543-1551
Number of pages9
JournalBiological Chemistry
Volume384
Issue number12
DOIs
Publication statusPublished - 1 Dec 2003

Keywords

  • Diabetes
  • Dipeptidyl peptides IV
  • GLP-1
  • Insulin secretion

Fingerprint

Dive into the research topics of 'Metabolic stability, receptor binding, cAMP generation, insulin secretion and antihyperglycaemic activity of novel N-terminal Glu9-substituted analogues of glucagon-like peptide-1'. Together they form a unique fingerprint.

Cite this