Cited by 119Pancreatic function and diabetesCancer, Hypoxia, and MetabolismDiabetes and associated disorders

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The hypoxia response pathway and β ‐cell function

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Cantley, J., Grey, S. T., Maxwell, P. H., Withers, D. J.·2010·Diabetes, Obesity and Metabolism

DOI 10.1111/j.1463-1326.2010.01276.x

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Abstract

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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High Seeding Density Induces Local Hypoxia and Triggers a Proinflammatory Response in Isolated Human Islets
Brandhorst, D., Brandhorst, H., Mullooly, N., Acreman, S., & Johnson, P. R. V. (2016) · Cell Transplantation · doi:10.3727/096368915x689929 · Cited by 22
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Background
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The role of α-ketoglutarate and the hypoxia sensing pathway in the regulation of pancreatic β-cell function
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Elimination of Von Hippel-Lindau Function Perturbs Pancreas Endocrine Homeostasis in Mice
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Background
Sweet and Sour β-Cells: ROS and Hif1α Induce Warburg-Like Lactate Production During Type 2 Diabetes
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BackgroundSelf-citation
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Wang, X., Brielle, S., Kenty, J. H.-R., Korover, N., Bavli, D., Pop, R., & Melton, D. A. (2025) · Nature Communications · doi:10.1038/s41467-025-59924-7 · Cited by 14
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3D printed VEGF-CPO biomaterial scaffold to promote subcutaneous vascularization and survival of transplanted islets for the treatment of diabetes
Chen, X., Wang, K., Han, Y., Pan, Q., Jiang, X., Yu, Z., Zhang, W., Wang, Z., Yan, H., Sun, P., et al. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.132376 · Cited by 10
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Self-citation
Hyperoxia reduces insulin release and induces mitochondrial dysfunction with possible implications for hyperoxic treatment of neonates
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Background
Pancreatic Islet Transplantation Technologies: State of the Art of Micro- and Macro-Encapsulation
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Overexpression of HIF-2α in pancreatic β cells does not alter glucose homeostasis
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Oxygen-permeable microwell device maintains islet mass and integrity during shipping
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“These transcriptional changes are conserved in model species (rat and mouse) (62, 63, 64).”
BackgroundSelf-citation
Human amniotic mesenchymal stem cell-islet organoids enhance the efficiency of islet engraftment in a mouse diabetes model
Zhou, J.-X., Jie-Zhou, Jin, W.-R., Li, J., Zhang, X.-C., Zhao, C.-Y., Lin, Y.-Y., Wang, X., Yan, L.-F., Kaiyan, et al. (2024) · Life Sciences · doi:10.1016/j.lfs.2024.122812 · Cited by 8
Preconditioned human dental pulp stem cells with cerium and yttrium oxide nanoparticles effectively ameliorate diabetic hyperglycemia while combatting hypoxia.
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Metabolic Stress and Adaptation in Pancreatic β-Cells to Hypoxia: Mechanisms, Modulators, and Implications for Transplantation
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Metabolic Stress Impairs Pericyte Response to Optogenetic Stimulation in Pancreatic Islets
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Background
Pre-adaptation of stem cell-derived islet organoids to hypoxia via zinc transportation inhibition drives angiogenesis
Wang, Z., Xu, M., Hu, R., Chen, X., Wang, X., Shi, G., Lu, S., Yang, Y., Su, Y., Gong, M., et al. (2026) · Cell stem cell · doi:10.1016/j.stem.2026.03.004 · Cited by 5
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Jeyagaran, A., Urbanczyk, M., Carvajal-Berrio, D. A., Baldissera, T., Kaiser, P., Kuhlburger, L., Czemmel, S., Nahnsen, S., Duffy, G., Brucker, S., et al. (2024) · Advanced Healthcare Materials · doi:10.1002/adhm.202403017 · Cited by 4
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Brandhorst, D., Brandhorst, H., Acreman, S., & Johnson, P. R. V. (2022) · Scientific Reports · doi:10.1038/s41598-022-23862-x · Cited by 4
Augmenting engraftment of beta cell replacement therapies for T1DM
Aggarwal, S., Pepper, A. R., & Jahdhami, N. A. (2021) · Journal of Immunology and Regenerative Medicine · doi:10.1016/j.regen.2021.100058 · Cited by 5
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“This is an open access article under active, resulting in slower glucose uptake and a change to predominantly anaerobic glycolysis, with pyruvate directed to lactate rather than ATP production, glucose sensing and insulin secretion will be compromised (Cantley et al., 2010).”
Background
Oxygen-releasing scaffolds in tissue engineering: design strategies, fabrication and regenerative applications
Shang, Y., Wang, L., Shen, H., Jia, M., Gao, H., Liu, Y., Yang, Y., Yang, J., Wu, L.-L., & Li, G.-C. (2026) · Regenerative Biomaterials · doi:10.1093/rb/rbag096 · Cited by 1
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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.
ORCID: Cantley, J.
Grey, S. T.
Maxwell, P. H.
Withers, D. 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
DOI: 10.1111/j.1463-1326.2010.01276.x
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
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
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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The hypoxia response pathway and β ‐cell function

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