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Original Articles

The Gly40Ser Mutation in the Human Glucagon Receptor Gene Associated With NIDDM Results in a Receptor With Reduced Sensitivity to Glucagon

  1. Lars H Hansen,
  2. Niels Abrahamsen,
  3. Jörg Hager,
  4. Laura Jelinek,
  5. Wayne Kindsvogel,
  6. Philippe Froguel and
  7. Erica Nishimura
  1. Department of Molecular Signalling, Hagedorn Research Institute Gentofte, Denmark
  2. CNRS EP10 Institut Pasteur et C.H.U. Lille, France
  3. ZymoGenetics, Inc. Seattle, Washington
  1. Address correspondence and reprint requests to Dr. Erica Nishimura, Department of Molecular Signalling, Hagedorn Research Institute, Niels Steensens Vej 6, DK 2820, Gentofte, Denmark.
Diabetes 1996 Jun; 45(6): 725-730. https://doi.org/10.2337/diab.45.6.725
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Abstract

The pancreatic islet hormone, glucagon, stimulates hepatic glucose production and has also been shown to potentiate glucose-induced insulin secretion. Because glucagon is a key regulator of glucose homeostasis, its receptor, which mediates the actions of glucagon, was considered a candidate gene involved in the pathogenesis of NIDDM. We have previously reported that a single heterozygous missense mutation in exon 2 of the glucagon receptor gene, which changes a glycine to a serine (Gly40Ser), is associated with NIDDM in a French population. In the present study, the signaling properties of this mutant receptor were examined in baby hamster kidney cells and rat insulinoma cells (REV-5AH) stably transfected with either the wild type or Gly40Ser mutant human glucagon receptor cDNAs. Competition assays using 125 I-labeled glucagon were performed, and in both cell types, the Gly40Ser mutant receptor was found to bind glucagon with an approximately threefold lower affinity compared with the wild type receptor. In both cell types, the production of cAMP in response to glucagon was decreased in cells expressing the mutant receptor compared with those expressing the wild type. Finally, glucagon-stimulated insulin secretion by RIN cells expressing the mutant receptor was decreased such that the dose-response curve was shifted to the right in comparison to that obtained with cells expressing the wild type receptor. These results indicate that this single-point mutation located in the extracellular region of the glucagon receptor decreases the sensitivity of target tissues to glucagon.

  • Received October 6, 1995.
  • Revision received January 18, 1996.
  • Accepted January 18, 1996.
  • Copyright © 1996 by the American Diabetes Association

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June 1996, 45(6)
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The Gly40Ser Mutation in the Human Glucagon Receptor Gene Associated With NIDDM Results in a Receptor With Reduced Sensitivity to Glucagon
Lars H Hansen, Niels Abrahamsen, Jörg Hager, Laura Jelinek, Wayne Kindsvogel, Philippe Froguel, Erica Nishimura
Diabetes Jun 1996, 45 (6) 725-730; DOI: 10.2337/diab.45.6.725

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The Gly40Ser Mutation in the Human Glucagon Receptor Gene Associated With NIDDM Results in a Receptor With Reduced Sensitivity to Glucagon
Lars H Hansen, Niels Abrahamsen, Jörg Hager, Laura Jelinek, Wayne Kindsvogel, Philippe Froguel, Erica Nishimura
Diabetes Jun 1996, 45 (6) 725-730; DOI: 10.2337/diab.45.6.725
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