THE GLY40SER MUTATION IN THE HUMAN GLUCAGON RECEPTOR GENE ASSOCIATED WITH NIDDM RESULTS IN A RECEPTOR WITH REDUCED SENSITIVITY TO GLUCAGON

The pancreatic islet hormone, glucagon, stimulates hepatic glucose pro duction 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 previo usly reported that a single heterozygous missense mutation in exon 2 o f the glucagon receptor gene, which changes a glycine to a serine (Gly 40Ser), is associated with NIDDM in a French population, In the presen t study, the signaling properties of this mutant receptor were examine d in baby hamster kidney cells and rat insulinoma cells (RIN-5AH) stab ly transfected with either the wild type or Gly40Ser mutant human gluc agon receptor cDNAs, Competition assays using I-125-labeled glucagon w ere performed, and in both cell types, the Gly40Ser mutant receptor wa s found to bind glucagon with an approximately threefold lower affinit y compared with the wild type receptor, In both cell. types, tile prod uction of cAMP in response to glucagon was decreased in cells expressi ng the mutant receptor compared with those expressing the wild type, F inally, glucagon-stimulated insulin secretion by RIN cells expressing the mutant receptor was decreased such that the dose-response curve wa s shifted to the right in comparison to that obtained with cells expre ssing the wild type receptor. These results indicate that this single- point mutation located in the extracellular region of the glucagon rec eptor decreases the sensitivity of target tissues to glucagon.