title: A role for von Hippel-Lindau protein in pancreatic beta-cell function.
abstract: OBJECTIVE
  The Vhlh gene codes for the von Hippel-Lindau protein (VHL), a tumor suppressor that is a key player in the cellular response to oxygen sensing. In humans, a germline mutation in the VHL gene leads to the von Hippel-Lindau disease, a familial syndrome characterized by benign and malignant tumors of the kidney, central nervous system, and pancreas.
  
  
  METHODS
  We use Cre-lox recombination to eliminate Vhlh in adult mouse pancreatic beta-cells. Morphology of mutant islets is assessed by immunofluorescence analysis. To determine the functional state of Vhlh(-/-) islets, insulin secretion is measured in vivo and in vitro, and quantitative PCR is used to identify changes in gene expression.
  
  
  RESULTS
  Loss of VHL in beta-cells leads to a severe glucose-intolerant phenotype in adult animals. Although VHL is not required for beta-cell specification and development, it is critical for beta-cell function. Insulin production is normal in beta-cells lacking VHL; however, insulin secretion in the presence of high concentrations of glucose is impaired. Furthermore, the loss of VHL leads to dysregulation of glycolytic enzymes, pointing to a perturbation of the intracellular energy homeostasis.
  
  
  CONCLUSIONS
  We show that loss of VHL in beta-cells leads to defects in glucose homeostasis, indicating an important and previously unappreciated role for VHL in beta-cell function. We believe that the beta-cell-specific Vhlh-deficient mice might be a useful tool as a "genetic hypoxia" model, to unravel the possible link between hypoxia signaling and impairment of beta-cell function.
authors.affiliation: Diabetes Center, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Sapna
authors.initials: S
authors.lastname: Puri
authors.forename: David A
authors.initials: DA
authors.lastname: Cano
authors.forename: Matthias
authors.initials: M
authors.lastname: Hebrok
mesh_terms: D000818:Animals; D005455:Fluorescent Antibody Technique; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D016133:Polymerase Chain Reaction; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000502:physiology*
chemical_list: D007328:Insulin; D051794:Von Hippel-Lindau Tumor Suppressor Protein