title: Pancreatic α-cell hyperplasia and hyperglucagonemia due to a glucagon receptor splice mutation.
abstract: Glucagon stimulates hepatic glucose production by activating specific glucagon receptors in the liver, which in turn increase hepatic glycogenolysis as well as gluconeogenesis and ureagenesis from amino acids. Conversely, glucagon secretion is regulated by concentrations of glucose and amino acids. Disruption of glucagon signaling in rodents results in grossly elevated circulating glucagon levels but no hypoglycemia. Here, we describe a patient carrying a homozygous G to A substitution in the invariant AG dinucleotide found in a 3' mRNA splice junction of the glucagon receptor gene. Loss of the splice site acceptor consensus sequence results in the deletion of 70 nucleotides encoded by exon 9, which introduces a frame shift and an early termination signal in the receptor mRNA sequence. The mutated receptor neither bound125I-labeled glucagon nor induced cAMP production upon stimulation with up to 1 µM glucagon. Despite the mutation, the only obvious pathophysiological trait was hyperglucagonemia, hyperaminoacidemia and massive hyperplasia of the pancreatic α-cells assessed by histology. Our case supports the notion of a hepato-pancreatic feedback system, which upon disruption leads to hyperglucagonemia and α-cell hyperplasia, as well as elevated plasma amino acid levels. Together with the glucagon-induced hypoaminoacidemia in glucagonoma patients, our case supports recent suggestions that amino acids may provide the feedback link between the liver and the pancreatic α-cells.
  
  
  CONCLUSIONS
  Loss of function of the glucagon receptor may not necessarily lead to the dysregulation of glucose homeostasis.Loss of function of the glucagon receptor causes hyperaminoacidemia, hyperglucagonemia and α-cell hyperplasia and sometimes other pancreatic abnormalities.A hepato-pancreatic feedback regulation of the α-cells, possibly involving amino acids, may exist in humans.
authors.affiliation: Department of Diabetology , Hôpital Bichat and University Paris Denis Diderot, Paris , France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Larger
authors.affiliation: Department of Biomedical Sciences; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Nicolai J
authors.initials: NJ
authors.lastname: Wewer Albrechtsen
authors.affiliation: Department of Molecular Signaling , Hagedorn Research Institute, Gentofte , Denmark.
authors.forename: Lars H
authors.initials: LH
authors.lastname: Hansen
authors.affiliation: Department of Medicine , Yong Loo Lin School of Medicine, National University of Singapore , Singapore.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Gelling
authors.affiliation: Inserm UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France; Sorbonne University, UPMC, University of Paris 6, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Capeau
authors.affiliation: Department of Biomedical Sciences; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Carolyn F
authors.initials: CF
authors.lastname: Deacon
authors.affiliation: Global Research External Affairs , Novo Nordisk A/S, 2760 Måløv , Denmark.
authors.forename: Ole D
authors.initials: OD
authors.lastname: Madsen
authors.affiliation: Department of Internal Medicine, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan; Department of Education Planning and Development, Faculty of Medicine, Toho University, Tokyo, Japan.
authors.forename: Fumiatsu
authors.initials: F
authors.lastname: Yakushiji
authors.affiliation: Global Research External Affairs , Novo Nordisk A/S, 2760 Måløv , Denmark.
authors.forename: Pierre
authors.initials: P
authors.lastname: De Meyts
authors.affiliation: Department of Biomedical Sciences; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Holst
authors.affiliation: Metabolic Disease Research , Novo Nordisk A/S, Måløv , Denmark.
authors.forename: Erica
authors.initials: E
authors.lastname: Nishimura