Metabolic Stability, Receptor Binding, cAMP Generation, Insulin Secretion and Antihyperglycaemic Activity of Novel N-Terminal Glu9-Substituted Analogues of Glucagon-Like Peptide-1
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| 024 | 7 | 0 | |a 10.1515/BC.2003.171 |2 doi |
| 035 | |a (NATIONALLICENCE)gruyter-10.1515/BC.2003.171 | ||
| 245 | 0 | 0 | |a Metabolic Stability, Receptor Binding, cAMP Generation, Insulin Secretion and Antihyperglycaemic Activity of Novel N-Terminal Glu9-Substituted Analogues of Glucagon-Like Peptide-1 |h [Elektronische Daten] |c [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] |
| 520 | 3 | |a 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. | |
| 540 | |a Copyright © 2003 by Walter de Gruyter GmbH & Co. KG | ||
| 690 | 7 | |a Biochemistry |2 nationallicence | |
| 690 | 7 | |a Molecular biology |2 nationallicence | |
| 690 | 7 | |a Cellular biology |2 nationallicence | |
| 700 | 1 | |a Green |D B. D. |4 aut | |
| 700 | 1 | |a Gault |D V. A. |4 aut | |
| 700 | 1 | |a Irwin |D N. |4 aut | |
| 700 | 1 | |a Mooney |D M. H. |4 aut | |
| 700 | 1 | |a Bailey |D C. J. |4 aut | |
| 700 | 1 | |a Harriott |D P. |4 aut | |
| 700 | 1 | |a Greer |D B. |4 aut | |
| 700 | 1 | |a Flatt |D P. R. |4 aut | |
| 700 | 1 | |a O'Harte |D F. P. M. |4 aut | |
| 773 | 0 | |t Biological Chemistry |d Walter de Gruyter |g 384/12(2003-12-25), 1543-1551 |x 1431-6730 |q 384:12<1543 |1 2003 |2 384 |o bchm | |
| 856 | 4 | 0 | |u https://doi.org/10.1515/BC.2003.171 |q text/html |z Onlinezugriff via DOI |
| 908 | |D 1 |a research article |2 jats | ||
| 950 | |B NATIONALLICENCE |P 856 |E 40 |u https://doi.org/10.1515/BC.2003.171 |q text/html |z Onlinezugriff via DOI | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Green |D B. D. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Gault |D V. A. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Irwin |D N. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Mooney |D M. H. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Bailey |D C. J. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Harriott |D P. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Greer |D B. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Flatt |D P. R. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a O'Harte |D F. P. M. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 773 |E 0- |t Biological Chemistry |d Walter de Gruyter |g 384/12(2003-12-25), 1543-1551 |x 1431-6730 |q 384:12<1543 |1 2003 |2 384 |o bchm | ||
| 900 | 7 | |b CC0 |u http://creativecommons.org/publicdomain/zero/1.0 |2 nationallicence | |
| 898 | |a BK010053 |b XK010053 |c XK010000 | ||
| 949 | |B NATIONALLICENCE |F NATIONALLICENCE |b NL-gruyter | ||