caa a22 4500 378856022 CHVBK 20180305123335.0 cr unu---uuuuu 161128e20031225xx s 000 0 eng 10.1515/BC.2003.171 doi (NATIONALLICENCE)gruyter-10.1515/BC.2003.171 Metabolic Stability, Receptor Binding, cAMP Generation, Insulin Secretion and Antihyperglycaemic Activity of Novel N-Terminal Glu9-Substituted Analogues of Glucagon-Like Peptide-1 [Elektronische Daten] [B. D. Green, V. A. Gault, N. Irwin, M. H. Mooney, C. J. Bailey, P. Harriott, B. Greer, P. R. Flatt, F. P. M. O'Harte] 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 DPPIV 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. Copyright © 2003 by Walter de Gruyter GmbH & Co. KG Biochemistry nationallicence Molecular biology nationallicence Cellular biology nationallicence Green B. D. aut Gault V. A. aut Irwin N. aut Mooney M. H. aut Bailey C. J. aut Harriott P. aut Greer B. aut Flatt P. R. aut O'Harte F. P. M. aut Biological Chemistry Walter de Gruyter 384/12(2003-12-25), 1543-1551 1431-6730 384:12<1543 2003 384 bchm https://doi.org/10.1515/BC.2003.171 text/html Onlinezugriff via DOI 1 research article jats NATIONALLICENCE 856 40 https://doi.org/10.1515/BC.2003.171 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Green B. D. aut NATIONALLICENCE 700 1- Gault V. A. aut NATIONALLICENCE 700 1- Irwin N. aut NATIONALLICENCE 700 1- Mooney M. H. aut NATIONALLICENCE 700 1- Bailey C. J. aut NATIONALLICENCE 700 1- Harriott P. aut NATIONALLICENCE 700 1- Greer B. aut NATIONALLICENCE 700 1- Flatt P. R. aut NATIONALLICENCE 700 1- O'Harte F. P. M. aut NATIONALLICENCE 773 0- Biological Chemistry Walter de Gruyter 384/12(2003-12-25), 1543-1551 1431-6730 384:12<1543 2003 384 bchm CC0 http://creativecommons.org/publicdomain/zero/1.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-gruyter