Deletion of the von Hippel–Lindau gene in pancreatic β cells impairs glucose homeostasis in mice
James Cantley, Colin Selman, Deepa Shukla, Andrey Y. Abramov, Frauke Forstreuter, Miguel A. Esteban, Marc Claret, Steven J. Lingard, Melanie Clements, Sarah K. Harten, Henry Asare-Anane, Rachel L. Batterham, Pedro L. Herrera, Shanta J. Persaud, Michael R. Duchen, Patrick H. Maxwell, Dominic J. Withers
James Cantley, Colin Selman, Deepa Shukla, Andrey Y. Abramov, Frauke Forstreuter, Miguel A. Esteban, Marc Claret, Steven J. Lingard, Melanie Clements, Sarah K. Harten, Henry Asare-Anane, Rachel L. Batterham, Pedro L. Herrera, Shanta J. Persaud, Michael R. Duchen, Patrick H. Maxwell, Dominic J. Withers
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Research Article Metabolism

Deletion of the von Hippel–Lindau gene in pancreatic β cells impairs glucose homeostasis in mice

Abstract

Defective insulin secretion in response to glucose is an important component of the β 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 β cells, we generated mice lacking Vhl in pancreatic β cells (βVhlKO 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 β cells or the pancreas altered expression of genes involved in β cell function, including those involved in glucose transport and glycolysis, and isolated βVhlKO and PVhlKO islets displayed impaired glucose uptake and defective glucose metabolism. The abnormal glucose homeostasis was dependent on upregulation of Hif-1α expression, and deletion of Hif1a in Vhl-deficient β cells restored GSIS. Consistent with this, expression of activated Hif-1α in a mouse β 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 β cell dysfunction.

Authors

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

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Figure 1

Deletion of Vhl in β cells or the pancreas impairs glucose homeostasis in mice.

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Deletion of Vhl in β cells or the pancreas impairs glu...
(A) Recombination of the Vhl allele was assayed by PCR in islets, cerebral cortex (cortex), and hypothalami (hyp) from WT and KO mice for βVhlKO and PVhlKO mice. Positive and negative PCR controls for deletion were performed using DNA from Vhl-null cells, Vhl control (cont) cells, WT cells, and without addition of DNA. Arrows indicate the deleted allele. (B and C) Hif-1α staining using chromogenic detection (left and middle panels) in islets from control, βVhlKO, and PVhlKO mice and combined chromogenic/immunofluorescence staining (right panels) co-localizing Hif-1α and insulin in islets from βVhlKO and PVhlKO mice. (D and E) Fed blood glucose levels in 12-week-old female control, βVhlKO, and PVhlKO mice. n = 8. (F and G) Blood glucose after an intraperitoneal injection (2 g/kg body weight) of glucose in 12-week-old female control, βVhlKO, and PVhlKO mice. n = 8 for null alleles; n = 24 for control animals. (H and I) Fed plasma insulin levels in 12-week-old female control, βVhlKO, and PVhlKO mice. n = 8. *P < 0.05, **P < 0.01, ***P < 0.001 compared with control.