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

作者：Cantley James; Selman Colin; Shukla Deepa; Abramov Andrey Y; Forstreuter Frauke; Esteban Miguel A; Claret Marc; Lingard Steven J; Clements Melanie; Harten Sarah K; Asare Anane Henry; Batterham Rachel L; Herrera Pedro L; Persaud Shanta J; Duchen Michael R; Maxwell Patrick H; Withers Dominic J^*

来源：Journal of Clinical Investigation, 2009, 119(1): 125-135.

DOI：10.1172/JCI26934

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.

• 出版日期2009-1