Deletion of the von Hippel--Lindau gene in pancreatic [beta] cells impairs glucose homeostasis in mice

Defective insulin secretion in response to glucose is an important component of the [beta] cell dysfunction seen in type 2 diabetes. As mitochondrial oxidative phosphorylation plays a key role in glucose-stimulated insulin secretion (GSIS), oxygen-sensing pathways may modulate insulin release. The von Hippel--Lindau (VHL) protein controls the degradation of hypoxia-inducible factor (HIF) to coordinate cellular and organismal responses to altered oxygenation. To determine the role of this pathway in controlling glucose-stimulated insulin release from pancreatic [beta] cells, we generated mice lacking Vhl in pancreatic [beta] cells ([beta]VhlKO mice) and mice lacking Vhl in the pancreas (PVhlKO mice). Both mouse strains developed glucose intolerance with impaired insulin secretion. Furthermore, deletion of Vhl in [beta] cells or the pancreas altered expression of genes involved in [beta] cell function, including those involved in glucose transport and glycolysis, and isolated [beta]VhlKO and PVhlKO islets displayed impaired glucose uptake and defective glucose metabolism. The abnormal glucose homeostasis was dependent on upregulation of Hif-1[alpha] expression, and deletion of Hif1a in Vhl-deficient [beta] cells restored GSIS. Consistent with this, expression of activated Hif-1[alpha] in a mouse [beta] cell line impaired GSIS. These data suggest that VHL/HIF oxygen-sensing mechanisms play a critical role in glucose homeostasis and that activation of this pathway in response to decreased islet oxygenation may contribute to [beta] cell dysfunction.
Introduction Blood glucose levels are normally tightly controlled by the regulation of insulin release from the pancreatic [beta] cells. Glucose-stimulated insulin secretion (GSIS) is a complex metabolic process involving the [...]