Degradation, receptor binding, insulin secreting and antihyperglycaemic actions of palmitate-derivatised native and Ala8-substituted GLP-1 analogues
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| 024 | 7 | 0 | |a 10.1515/BC.2004.035 |2 doi |
| 035 | |a (NATIONALLICENCE)gruyter-10.1515/BC.2004.035 | ||
| 245 | 0 | 0 | |a Degradation, receptor binding, insulin secreting and antihyperglycaemic actions of palmitate-derivatised native and Ala8-substituted GLP-1 analogues |h [Elektronische Daten] |c [B. D. Green, V. A. Gault, M. H. Mooney, N. Irwin, P. Harriott, B. Greer, C. J. Bailey, F. P. M. O'Harte, P. R. Flatt] |
| 520 | 3 | |a The hormone glucagon-like peptide-1(736)amide (GLP-1) is released in response to ingested nutrients and acts to promote glucose-dependent insulin secretion ensuring efficient postprandial glucose homeostasis. Unfortunately, the beneficial actions of GLP-1 which give this hormone many of the desirable properties of an antidiabetic drug are short lived due to degradation by dipeptidylpeptidase IV (DPP IV) and rapid clearance by renal filtration. In this study we have attempted to extend GLP-1 action through the attachment of palmitoyl moieties to the ?amino group in the side chain of the Lys26 residue and to combine this modification with substitutions of the Ala8 residue, namely Val or aminobutyric acid (Abu). In contrast to native GLP-1, which was rapidly degraded, [Lys(pal)26]GLP-1, [Abu8,Lys(pal)26]GLP-1 and [Val8,Lys(pal)26]GLP-1 all exhibited profound stability during 12 h incubations with DPP IV and human plasma. Receptor binding affinity and the ability to increase cyclic AMP in the clonal ?cell line BRINBD11 were decreased by 86- to 167-fold and 15- to 62-fold, respectively compared with native GLP-1. However, insulin secretory potency tested using BRINBD11 cells was similar, or in the case of [Val8,Lys(pal)26]GLP-1 enhanced. Furthermore, when administered in vivo together with glucose to diabetic (ob/ob) mice, [Lys(pal)26]GLP-1, [Abu8,Lys(pal)26]GLP-1 and [Val8,Lys(pal)26]GLP-1 did not demonstrate acute glucoselowering or insulinotropic activity as observed with native GLP-1. These studies support the potential usefulness of fatty acid linked analogues of GLP-1 but indicate the importance of chain length for peptide kinetics and bioavailability. | |
| 540 | |a Copyright © 2004 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 Mooney |D M. H. |4 aut | |
| 700 | 1 | |a Irwin |D N. |4 aut | |
| 700 | 1 | |a Harriott |D P. |4 aut | |
| 700 | 1 | |a Greer |D B. |4 aut | |
| 700 | 1 | |a Bailey |D C. J. |4 aut | |
| 700 | 1 | |a O'Harte |D F. P. M. |4 aut | |
| 700 | 1 | |a Flatt |D P. R. |4 aut | |
| 773 | 0 | |t Biological Chemistry |d Walter de Gruyter |g 385/2(2004-02-05), 169-177 |x 1431-6730 |q 385:2<169 |1 2004 |2 385 |o bchm | |
| 856 | 4 | 0 | |u https://doi.org/10.1515/BC.2004.035 |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.2004.035 |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 Mooney |D M. H. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Irwin |D N. |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 Bailey |D C. J. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a O'Harte |D F. P. M. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Flatt |D P. R. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 773 |E 0- |t Biological Chemistry |d Walter de Gruyter |g 385/2(2004-02-05), 169-177 |x 1431-6730 |q 385:2<169 |1 2004 |2 385 |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 | ||