Document Detail

Degradation, receptor binding, insulin secreting and antihyperglycaemic actions of palmitate-derivatised native and Ala8-substituted GLP-1 analogues.
MedLine Citation:
PMID:  15101559     Owner:  NLM     Status:  MEDLINE    
The hormone glucagon-like peptide-1(7-36)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 dipeptidyl-peptidase 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 epsilon-amino group in the side chain of the Lys26 residue and to combine this modification with substitutions of the Ala8 residue, namely Val or amino-butyric 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 beta-cell line BRIN-BD11 were decreased by 86- to 167-fold and 15- to 62-fold, respectively compared with native GLP-1. However, insulin secretory potency tested using BRIN-BD11 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 glucose-lowering 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.
Brian D Green; Victor A Gault; Mark H Mooney; Nigel Irwin; Patrick Harriott; Brett Greer; Cliff J Bailey; Finbarr P M O'Harte; Peter R Flatt
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biological chemistry     Volume:  385     ISSN:  1431-6730     ISO Abbreviation:  Biol. Chem.     Publication Date:  2004 Feb 
Date Detail:
Created Date:  2004-04-22     Completed Date:  2004-05-19     Revised Date:  2013-03-19    
Medline Journal Info:
Nlm Unique ID:  9700112     Medline TA:  Biol Chem     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  169-77     Citation Subset:  IM    
School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK.
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MeSH Terms
Alanine / chemistry,  metabolism
Blood Glucose / metabolism
Cell Line
Cyclic AMP / biosynthesis
Dipeptidyl Peptidase 4 / metabolism
Glucagon / blood,  chemistry,  pharmacokinetics*,  pharmacology*
Glucagon-Like Peptide 1
Hypoglycemic Agents / chemistry,  pharmacokinetics,  pharmacology
Injections, Intraperitoneal
Insulin / metabolism,  secretion*
Islets of Langerhans / drug effects,  secretion
Lysine / chemistry
Mice, Obese
Palmitates / chemistry*,  pharmacokinetics,  pharmacology
Peptide Fragments / blood,  chemistry,  pharmacokinetics*,  pharmacology*
Protein Precursors / blood,  chemistry,  pharmacokinetics*,  pharmacology*
Radioligand Assay
Receptors, Glucagon / metabolism
Valine / chemistry
Reg. No./Substance:
0/Blood Glucose; 0/Hypoglycemic Agents; 0/Insulin; 0/Palmitates; 0/Peptide Fragments; 0/Protein Precursors; 0/Receptors, Glucagon; 0/glucagon-like peptide-1 receptor; 56-41-7/Alanine; 56-87-1/Lysine; 60-92-4/Cyclic AMP; 7004-03-7/Valine; 89750-14-1/Glucagon-Like Peptide 1; 9007-92-5/Glucagon; EC Peptidase 4

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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