caa a22 4500 378893149 CHVBK 20180305123500.0 cr unu---uuuuu 161128e20040205xx s 000 0 eng 10.1515/BC.2004.035 doi (NATIONALLICENCE)gruyter-10.1515/BC.2004.035 Degradation, receptor binding, insulin secreting and antihyperglycaemic actions of palmitate-derivatised native and Ala8-substituted GLP-1 analogues [Elektronische Daten] [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] 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. Copyright © 2004 by Walter de Gruyter GmbH & Co. KG Biochemistry nationallicence Molecular biology nationallicence Cellular biology nationallicence Green B. D. aut Gault V. A. aut Mooney M. H. aut Irwin N. aut Harriott P. aut Greer B. aut Bailey C. J. aut O'Harte F. P. M. aut Flatt P. R. aut Biological Chemistry Walter de Gruyter 385/2(2004-02-05), 169-177 1431-6730 385:2<169 2004 385 bchm https://doi.org/10.1515/BC.2004.035 text/html Onlinezugriff via DOI 1 research article jats NATIONALLICENCE 856 40 https://doi.org/10.1515/BC.2004.035 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Green B. D. aut NATIONALLICENCE 700 1- Gault V. A. aut NATIONALLICENCE 700 1- Mooney M. H. aut NATIONALLICENCE 700 1- Irwin N. aut NATIONALLICENCE 700 1- Harriott P. aut NATIONALLICENCE 700 1- Greer B. aut NATIONALLICENCE 700 1- Bailey C. J. aut NATIONALLICENCE 700 1- O'Harte F. P. M. aut NATIONALLICENCE 700 1- Flatt P. R. aut NATIONALLICENCE 773 0- Biological Chemistry Walter de Gruyter 385/2(2004-02-05), 169-177 1431-6730 385:2<169 2004 385 bchm CC0 http://creativecommons.org/publicdomain/zero/1.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-gruyter