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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
J Clin Invest. 2009;
119(1):125
doi:10.1172/JCI26934
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D
efective 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.
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