title: Pancreatic neuroendocrine tumors in glucagon receptor-deficient mice.
abstract: Inhibition of glucagon signaling causes hyperglucagonemia and pancreatic α cell hyperplasia in mice. We have recently demonstrated that a patient with an inactivating glucagon receptor mutation (P86S) also exhibits hyperglucagonemia and pancreatic α cell hyperplasia but further develops pancreatic neuroendocrine tumors (PNETs). To test the hypothesis that defective glucagon signaling causes PNETs, we studied the pancreata of mice deficient in glucagon receptor (Gcgr(-/-)) from 2 to 12 months, using WT and heterozygous mice as controls. At 2-3 months, Gcgr(-/-) mice exhibited normal islet morphology but the islets were mostly composed of α cells. At 5-7 months, dysplastic islets were evident in Gcgr(-/-) mice but absent in WT or heterozygous controls. At 10-12 months, gross PNETs (≥1 mm) were detected in most Gcgr(-/-) pancreata and micro-PNETs (<1 mm) were found in all (n = 14), whereas the islet morphology remained normal and no PNETs were found in any WT (n = 10) or heterozygous (n = 25) pancreata. Most PNETs in Gcgr(-/-) mice were glucagonomas, but some were non-functioning. No tumors predominantly expressed insulin, pancreatic polypeptide, or somatostatin, although some harbored focal aggregates of tumor cells expressing one of those hormones. The PNETs in Gcgr(-/-) mice were well differentiated and occasionally metastasized to the liver. Menin expression was aberrant in most dysplatic islets and PNETs. Vascular endothelial growth factor (VEGF) was overexpressed in PNET cells and its receptor Flk-1 was found in the abundant blood vessels or blood islands inside the tumors. We conclude that defective glucagon signaling causes PNETs in the Gcgr(-/-) mice, which may be used as a model of human PNETs. Our results further suggest that completely inhibiting glucagon signaling may not be a safe approach to treat diabetes.
authors.affiliation: Division of Endocrinology, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America. run.yu@cshs.org
authors.forename: Run
authors.initials: R
authors.lastname: Yu
authors.forename: Deepti
authors.initials: D
authors.lastname: Dhall
authors.forename: Nicholas N
authors.initials: NN
authors.lastname: Nissen
authors.forename: Cuiqi
authors.initials: C
authors.lastname: Zhou
authors.forename: Song-Guang
authors.initials: SG
authors.lastname: Ren
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D048429:Cell Size; D004703:Endocrine System / Q000378:metabolism / Q000473:pathology; D006720:Homozygote; D006801:Humans; D006965:Hyperplasia; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D018358:Neuroendocrine Tumors / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D018027:Receptors, Glucagon / Q000172:deficiency* / Q000378:metabolism
chemical_list: C484898:Men1 protein, mouse; D011518:Proto-Oncogene Proteins; D018027:Receptors, Glucagon