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

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.
Authors	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
Journal	Biological chemistry (Biol Chem) Vol. 384 Issue 12 Pg. 1543-51 (Dec 2003) ISSN: 1431-6730 [Print] Germany
PMID	14719796 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Blood Glucose GLP1R protein, human Glp1r protein, mouse Glp1r protein, rat Glucagon-Like Peptide-1 Receptor Glycoproteins Hypoglycemic Agents Insulin Peptide Fragments Protein Precursors Receptors, Glucagon Glutamine Tyrosine Phenylalanine Glucagon-Like Peptide 1 Glucagon Proline Cyclic AMP DPP4 protein, human Dipeptidyl Peptidase 4 Adenosine Deaminase Glucose
Topics	Adenosine Deaminase (metabolism) Amino Acid Substitution Animals Binding, Competitive Blood Glucose (drug effects, metabolism) Cell Line, Tumor Cricetinae Cyclic AMP (metabolism) Diabetes Mellitus, Type 2 (drug therapy, metabolism) Dipeptidyl Peptidase 4 Fibroblasts (metabolism) Glucagon (genetics, metabolism, pharmacology) Glucagon-Like Peptide 1 Glucagon-Like Peptide-1 Receptor Glucose (pharmacology) Glutamine (chemistry) Glycoproteins (metabolism) Humans Hypoglycemic Agents (metabolism, pharmacology) Insulin (blood, metabolism) Insulin Secretion Islets of Langerhans (drug effects, metabolism) Mice Mice, Obese Peptide Fragments (genetics, metabolism, pharmacology) Phenylalanine (chemistry) Proline (chemistry) Protein Precursors (genetics, metabolism, pharmacology) Rats Receptors, Glucagon (metabolism) Spectrometry, Mass, Electrospray Ionization Transformation, Genetic Tyrosine (chemistry)

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