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The hypoxia response pathway and beta-cell function

Abstract

beta-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 beta-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 HIFalpha subunit for proteasomal degradation in the presence of oxygen. Several recent studies have shown that Vhl deletion in beta-cells results in Hif1alpha activation, impaired glucose-stimulated insulin secretion (GSIS) and glucose intolerance. This was found to be because of alterations in beta-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 beta-cell glucose sensing, other aspects of hypoxia signalling are discussed including beta-cell differentiation, development and vascularization. In conclusion, recent studies clearly show that hypoxia response mechanisms can negatively impact on glucose sensing mechanisms in the beta-cell and this has the potential to impair beta-cell function in a number of physiological and clinical situations.

Type Journal
ISBN 1463-1326 (Electronic) 1462-8902 (Linking)
Authors Cantley, J.; Grey, S. T.; Maxwell, P. H.; Withers, D. J.;
Responsible Garvan Author
Publisher Name DIABETES OBESITY & METABOLISM
Published Date 2010-01-01
Published Volume 12 Suppl 2
Published Pages 159-67
Status Published in-print
URL link to publisher's version http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21029313
OpenAccess link to author's accepted manuscript version https://publications.gimr.garvan.org.au/open-access/10901