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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
1-2
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pubmed:dateCreated |
2005-7-12
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pubmed:abstractText |
Glucagon-like peptide-1 (GLP-1) and its cognate receptor play an important physiological role in maintaining blood glucose homeostasis. A GLP-1 receptor (GLP-1R) polymorphism in which threonine 149 is substituted with a methionine residue has been recently identified in a patient with type 2 diabetes but was not found in non-diabetic control subjects. We have functionally assessed the recombinant GLP-1R variant after transient expression in COS-7 and HEK 293 cells. Compared to the wild type receptor, the variant GLP-1R showed (i) similar expression levels, (ii) 60-and 5-fold reduced binding affinities, respectively, for two GLP-1R full agonists, GLP-1 and exendin-4, and (iii) markedly decreased potencies of these peptides in triggering cAMP-mediated signaling (despite conserved efficacies). In contrast to full agonists, the efficacy of the primary GLP-1 metabolite/GLP-1R partial agonist, GLP-1 (9-36) amide, was essentially abolished by the T149M substitution. By hydropathy analysis, the polymorphism localizes to transmembrane domain 1, suggesting this receptor segment as a novel determinant of agonist affinity/efficacy. These findings reveal that naturally occurring sequence variability of the GLP-1R within the human population can result in substantial loss-of-function. A genetic link between the T149M variant and increased susceptibility to type 2 diabetes remains to be established.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Cyclic AMP,
http://linkedlifedata.com/resource/pubmed/chemical/DNA, Complementary,
http://linkedlifedata.com/resource/pubmed/chemical/Glucose,
http://linkedlifedata.com/resource/pubmed/chemical/Ligands,
http://linkedlifedata.com/resource/pubmed/chemical/Peptides,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, G-Protein-Coupled,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Glucagon,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Venoms,
http://linkedlifedata.com/resource/pubmed/chemical/exenatide,
http://linkedlifedata.com/resource/pubmed/chemical/glucagon-like peptide receptor
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0167-0115
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
15
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pubmed:volume |
130
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1-6
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pubmed:dateRevised |
2008-11-21
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pubmed:meshHeading |
pubmed-meshheading:15975668-Amino Acid Sequence,
pubmed-meshheading:15975668-Animals,
pubmed-meshheading:15975668-COS Cells,
pubmed-meshheading:15975668-Cell Line,
pubmed-meshheading:15975668-Cyclic AMP,
pubmed-meshheading:15975668-DNA, Complementary,
pubmed-meshheading:15975668-Dose-Response Relationship, Drug,
pubmed-meshheading:15975668-Genetic Predisposition to Disease,
pubmed-meshheading:15975668-Genetic Variation,
pubmed-meshheading:15975668-Glucose,
pubmed-meshheading:15975668-Homeostasis,
pubmed-meshheading:15975668-Humans,
pubmed-meshheading:15975668-Ligands,
pubmed-meshheading:15975668-Molecular Sequence Data,
pubmed-meshheading:15975668-Mutagenesis, Site-Directed,
pubmed-meshheading:15975668-Mutation,
pubmed-meshheading:15975668-Peptides,
pubmed-meshheading:15975668-Polymorphism, Genetic,
pubmed-meshheading:15975668-Receptors, G-Protein-Coupled,
pubmed-meshheading:15975668-Receptors, Glucagon,
pubmed-meshheading:15975668-Recombinant Proteins,
pubmed-meshheading:15975668-Sequence Homology, Amino Acid,
pubmed-meshheading:15975668-Signal Transduction,
pubmed-meshheading:15975668-Software,
pubmed-meshheading:15975668-Transcription, Genetic,
pubmed-meshheading:15975668-Venoms
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pubmed:year |
2005
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pubmed:articleTitle |
A human glucagon-like peptide-1 receptor polymorphism results in reduced agonist responsiveness.
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pubmed:affiliation |
Molecular Pharmacology Research Center, Molecular Cardiology Research Institute, Tufts-New England Medical Center, Mailbox 7703, 750 Washington Street, Boston, MA 02111, USA. MBeinborn@Tufts-NEMC.org
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, N.I.H., Extramural
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