Pancreatic neuroendocrine tumors in glucagon receptor-deficient mice

Academic Article

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. © 2011 Yu et al.
  • Authors

    Published In

  • PLoS One  Journal
  • Digital Object Identifier (doi)

    Pubmed Id

  • 26700703
  • Author List

  • Yu R; Dhall D; Nissen NN; Zhou C; Ren SG
  • Volume

  • 6
  • Issue

  • 8