title: Glucagon receptor is required for long-term survival: a natural history study of the Mahvash disease in a murine model.
abstract: OBJECTIVE
  We have described a novel Mahvash disease of hyperglucagonemia and pancreatic neuroendocrine tumors (PNETs) associated with an inactivating glucagon receptor mutation, and identified the glucagon receptor-deficient (Gcgr(-/-)) mice as its murine model. We aim to elucidate the natural history of the rare Mahvash disease by long-term observation of the Gcgr(-/-) mice.
  
  
  METHODS
  Wild type (WT) (n=52), heterozygous (n=127), and Gcgr(-/-) (n=56) mice living under standard vivarium conditions were observed without specific treatments over 22 months. Autopsy was performed on dead animals.
  
  
  RESULTS
  The WT and heterozygous mice did not exhibit any measurable differences. The Gcgr(-/-) mice became progressively lethargic and cachexic after 12 months. Random glucose levels were stable in WT and heterozygous mice but decreased with age in the Gcgr(-/-) mice. At the end of observation, 28/56 Gcgr(-/-), 7/52 WT, and 24/127 heterozygous mice died. The survival curve of Gcgr(-/-) mice began to separate from those of WT and heterozygous mice at 12 months and the survival difference widened with age. At 18 months, survival probability was 17% for Gcgr(-/-) mice but 77% for WT and 81% for heterozygous mice. Autopsy revealed numerous PNETs up to 15 mm in diameter in most well-preserved Gcgr(-/-) pancreata (17/20) but none in WT or heterozygous ones. Four Gcgr(-/-) mice developed liver or subcutaneous metastasis.
  
  
  CONCLUSIONS
  The untreated Mahvash disease may cause cachexia, severe hypoglycemia, and early death. Patients with Mahvash disease need to undergo life-long surveillance for PNETs. Functional glucagon receptor is thus required for long-term survival.
authors.affiliation: Division of Endocrinology and Carcinoid and Neuroendocrine Tumor Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA. run.yu@cshs.org
authors.forename: Run
authors.initials: R
authors.lastname: Yu
authors.forename: Song-Guang
authors.initials: SG
authors.lastname: Ren
authors.forename: James
authors.initials: J
authors.lastname: Mirocha
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002100:Cachexia / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005934:Glucagon / Q000097:blood* / Q000502:physiology; D006801:Humans; D007003:Hypoglycemia / Q000235:genetics; D053609:Lethargy / Q000235:genetics; D008113:Liver Neoplasms / Q000556:secondary; D008136:Longevity / Q000235:genetics; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics*; D018241:Neuroectodermal Tumors, Primitive, Peripheral / Q000235:genetics* / Q000556:secondary; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D018027:Receptors, Glucagon / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012878:Skin Neoplasms / Q000556:secondary
chemical_list: D001786:Blood Glucose; D018027:Receptors, Glucagon; D005934:Glucagon