Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we will assume that you are happy to receive all cookies and you will not see this message again. Click 'Find out more' for information on how to change your cookie settings.

β-cells sense glucose and secrete appropriate amounts of insulin by coupling glucose uptake and glycolysis with quantitative ATP production via mitochondrial oxidative pathways. Therefore, oxidative phosphorylation is essential for normal β-cell function. Multiple cell types adapt to hypoxia by inducing a transcriptional programme coordinated by the transcription factor hypoxia-inducible factor (HIF). HIF activity is regulated by the von Hippel-Lindau (Vhl) protein, which targets the HIFα subunit for proteasomal degradation in the presence of oxygen. Several recent studies have shown that Vhl deletion in β-cells results in Hif1α activation, impaired glucose-stimulated insulin secretion (GSIS) and glucose intolerance. This was found to be because of alterations in β-cell gene expression inducing a switch from aerobic glucose metabolism to anaerobic glycolysis, thus disrupting the GSIS triggering pathway. Situations in which islets may become hypoxic are discussed, in particular islet transplantation which has been reported to cause islet hypoxia because of an inadequate blood supply post-transplant. Aside from this principal role for HIF in negatively regulating β-cell glucose sensing, other aspects of hypoxia signalling are discussed including β-cell differentiation, development and vascularization. In conclusion, recent studies clearly show that hypoxia response mechanisms can negatively impact on glucose sensing mechanisms in the β-cell and this has the potential to impair β-cell function in a number of physiological and clinical situations.

Original publication

DOI

10.1111/j.1463-1326.2010.01276.x

Type

Journal article

Journal

Diabetes Obes Metab

Publication Date

10/2010

Volume

12 Suppl 2

Pages

159 - 167

Keywords

Animals, Blood Glucose, Cell Hypoxia, Glycolysis, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Insulin, Insulin-Secreting Cells, Mice, Oxygen, Phosphorylation, Von Hippel-Lindau Tumor Suppressor Protein, von Hippel-Lindau Disease