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.

RESEARCH DESIGN AND METHODS—We use Cre-lox recombination to eliminate Vhlh in adult mouse pancreatic β-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 β-cells leads to a severe glucose-intolerant phenotype in adult animals. Although VHL is not required for β-cell specification and development, it is critical for β-cell function. Insulin production is normal in β-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 β-cells leads to defects in glucose homeostasis, indicating an important and previously unappreciated role for VHL in β-cell function. We believe that the β-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 β-cell function.