A human glucagon-like peptide-1 receptor polymorphism results in reduced agonist responsiveness

Regul Pept. 2005 Aug 15;130(1-2):1-6. doi: 10.1016/j.regpep.2005.05.001.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Cell Line
  • Cyclic AMP / metabolism
  • DNA, Complementary / metabolism
  • Dose-Response Relationship, Drug
  • Exenatide
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Glucagon-Like Peptide-1 Receptor
  • Glucose / metabolism
  • Homeostasis
  • Humans
  • Ligands
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Mutation
  • Peptides / chemistry
  • Polymorphism, Genetic*
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Glucagon / agonists*
  • Receptors, Glucagon / genetics*
  • Recombinant Proteins / chemistry
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Software
  • Transcription, Genetic
  • Venoms / chemistry


  • DNA, Complementary
  • GLP1R protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Ligands
  • Peptides
  • Receptors, G-Protein-Coupled
  • Receptors, Glucagon
  • Recombinant Proteins
  • Venoms
  • Exenatide
  • Cyclic AMP
  • Glucose