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The hypoxia response pathway and β ‐cell function
Open accessAbstract
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 HIF α subunit for proteasomal degradation in the presence of oxygen. Several recent studies have shown that Vhl deletion in β ‐cells results in Hif1 α 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.
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“Hypoxic conditions and oxidative stress can also induce other stress pathways that result in β cell functional failure and apoptosis.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [133]
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Cites
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Total pancreatectomy with islet autotransplantation in children
Bellin, M. D., Schwarzenberg, S. J., Armfield, M., & Chinnakotla, S. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-814831-0.00007-5 · Cited by 2
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Speckmann, T. (2019) · doi:10.14288/1.0380061 · Cited by 1
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Divergent cell-type specific hypoxia responses in human stem cell-derived and primary islets
Bradley, K., Moore, C., Ishahak, M., Maestas, M. M., Veronese-Paniagua, D., & Millman, J. R. (2026) · Scientific Reports · doi:10.1038/s41598-026-52074-w · Cited by 2
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The prolyl hydroxylase PHD3 maintains β-cell glucose metabolism during fatty acid excessPreprint
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Metadata
- Authors
- Cantley, J., Grey, S. T., Maxwell, P. H., & Withers, D. J.
- Affiliations
- Garvan Institute of Medical Research (AU)
- University College London (GB)
- Corresponding author
- Cantley, J.
- Venue
- Diabetes, Obesity and Metabolism
- Publisher
- Wiley
- Published
- 2010-10
- Volume
- 12
- Issue
- s2
- Pages
- 159-167
- ISSN
- 1462-8902 (ISSN-L)
- 1463-1326
- OpenAlex
- W2084708745
- Cited by
- 119
- References
- 0
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 8 · 2023: 6 · 2022: 8 · 2021: 7 · 2020: 10 · 2019: 6 · 2018: 6 · 2017: 11 · 2016: 9 · 2015: 6 · 2014: 10 · 2013: 9 · 2012: 9
- FWCI
- 1.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes Obesity and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- hypoxia response, pancreatic beta cells, hypoxia-inducible factor, von Hippel-Lindau protein, HIF-1α, glucose-stimulated insulin secretion, glucose detection, oxidative phosphorylation, anaerobic glycolysis, islet transplantation, beta cell differentiation, islet vascularization, impaired glucose tolerance
- MeSH terms
- Insulin Secretion, Animals, Blood Glucose, Glycolysis, von Hippel-Lindau Disease, Humans, Insulin, Oxygen, Phosphorylation, Cell Hypoxia, Insulin-Secreting Cells, Mice, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit
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