Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Sies, Helmut / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred

12 Issues per year


IMPACT FACTOR 2016: 3.273

CiteScore 2016: 3.01

SCImago Journal Rank (SJR) 2016: 1.679
Source Normalized Impact per Paper (SNIP) 2016: 0.800

Online
ISSN
1437-4315
See all formats and pricing
More options …
Volume 385, Issue 2 (Feb 2004)

Issues

Degradation, receptor binding, insulin secreting and antihyperglycaemic actions of palmitate-derivatised native and Ala8-substituted GLP-1 analogues

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
Published Online: 2005-06-01 | DOI: https://doi.org/10.1515/BC.2004.035

Abstract

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.

About the article

Published Online: 2005-06-01

Published in Print: 2004-02-05


Citation Information: Biological Chemistry, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/BC.2004.035.

Export Citation

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

[1]
Lieming Ding, Sisi Lu, Yanping Wang, Haibo Chen, Wei Long, Cunbo Ma, Erlong He, Dan Yan, and Fenlai Tan
Pharmacological Research, 2017, Volume 122, Page 130
[2]
F. P. M. O'Harte, M. T. Ng, A. M. Lynch, J. M. Conlon, and P. R. Flatt
Diabetes, Obesity and Metabolism, 2016, Volume 18, Number 10, Page 1013
[3]
Xi-Rui Zhou, Qiang Zhang, Xi-Bo Tian, Yi-Meng Cao, Zhu-Qing Liu, Ruru Fan, Xiu-Fang Ding, Zhentai Zhu, Long Chen, and Shi-Zhong Luo
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2016, Volume 1858, Number 8, Page 1914
[4]
F.P.M. O'Harte, M.T. Ng, A.M. Lynch, J.M. Conlon, and P.R. Flatt
Molecular and Cellular Endocrinology, 2016, Volume 431, Page 133
[5]
Xiaohui Bai, Youhong Niu, Jingjing Zhu, An-Qi Yang, Yan-Fen Wu, and Xin-Shan Ye
Bioorganic & Medicinal Chemistry, 2016, Volume 24, Number 6, Page 1163
[6]
Brian Furman, Nigel Pyne, Peter Flatt, and Finbarr O'Harte
Journal of Pharmacy and Pharmacology, 2004, Volume 56, Number 12, Page 1477
[7]
Xibo Tian, Fude Sun, Xi-Rui Zhou, Shi-Zhong Luo, and Long Chen
Journal of Peptide Science, 2015, Volume 21, Number 7, Page 530
[8]
Bikash Manandhar and Jung-Mo Ahn
Journal of Medicinal Chemistry, 2015, Volume 58, Number 3, Page 1020
[9]
Long Chen and Jun F. Liang
Biomacromolecules, 2013, Volume 14, Number 7, Page 2326
[10]
Rachael Lennox, David W. Porter, Peter R. Flatt, and Victor A. Gault
ChemMedChem, 2013, Volume 8, Number 4, Page 595
[11]
B.D. Green, V.A. Gault, P.R. Flatt, P. Harriott, B. Greer, and F.P.M. O’Harte
Archives of Biochemistry and Biophysics, 2004, Volume 428, Number 2, Page 136
[12]
Long Chen, Zhigang Tu, Natalya Voloshchuk, and Jun F. Liang
Journal of Pharmaceutical Sciences, 2012, Volume 101, Number 4, Page 1508
[13]
Barry D. Kerr, Peter R. Flatt, and Victor A. Gault
Biochemical Pharmacology, 2010, Volume 80, Number 11, Page 1727
[14]
Nigel Irwin, Gillian C. Clarke, Brian D. Green, Brett Greer, Patrick Harriott, Victor A. Gault, Finbarr P.M. O’Harte, and Peter R. Flatt
Biochemical Pharmacology, 2006, Volume 72, Number 6, Page 719
[15]
Zhigang Tu, Jumin Hao, Riddhi Kharidia, Xiao G. Meng, and Jun F. Liang
Biochemical and Biophysical Research Communications, 2007, Volume 361, Number 3, Page 712
[17]
Nigel Irwin, Victor A. Gault, Brian D. Green, Brett Greer, Patrick Harriott, Clifford J. Bailey, Peter R. Flatt, and Finbarr P.M. O'Harte
Biological Chemistry, 2005, Volume 386, Number 7
[18]
Victor A. Gault, Kerry Hunter, Nigel Irwin, Brett Greer, Brian D. Green, Patrick Harriott, Finbarr P.M. O'Harte, and Peter R. Flatt
Biological Chemistry, 2007, Volume 388, Number 2
[19]
Dieter Hoersch, Joerg Schrader, and Ruediger Goeke
AfCS-Nature Molecule Pages, 2005
[20]
[21]
B. D. Green, H. K. Liu, J. T. McCluskey, N. A. Duffy, F. P. M. O'Harte, N. H. McClenaghan, and P R. Flatt
Diabetes, Obesity and Metabolism, 2005, Volume 7, Number 5, Page 563
[22]
Hongxiang Hui, Xiaoning Zhao, and Riccardo Perfetti
Diabetes/Metabolism Research and Reviews, 2005, Volume 21, Number 4, Page 313

Comments (0)

Please log in or register to comment.
Log in