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.
“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]
The Hypoxic Response section says hypoxia activates stress pathways beyond HIF, and Hypoxia-independent Activation of HIF says oxidative stress may activate HIF in β-cells and cause secretory dysfunction. The paper mentions apoptosis in connection with pro-inflammatory cytokines, but does not say that hypoxia- or oxidative-stress-induced pathways cause β-cell apoptosis. The indexed passages provide no page numbers. (LLM, conf=0.86)
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Potato Crop as a Source of Emetic Bacillus cereus and Cereulide-Induced Mammalian Cell Toxicity
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Impact of Pancreatic Rat Islet Density on Cell Survival during Hypoxia
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“There are recent data indicating that early hypoxic exposure may result in a persistent change in the human islet cell gene signature and longer-lasting loss of glucose-stimulated insulin secretion.(21,22) This becomes even more important if the islet does not completely revascularize, since this would mean that the i…”
BackgroundMicroenvironmental stimuli for proliferation of functional islet β-cells
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“Studies have shown that islet-like cell aggregates may suffer from hypoxia proportion to the radial distance inward leading to the cell necrosis and apoptosis as well as activation of the anaerobic metabolism [123].”
Backgroundβ-Klotho promotes glycolysis and glucose-stimulated insulin secretion via GP130
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“In addition, a compensatory increase in β-cell mass may compromise for the vascular density to maintain sufficient perfusion or oxygen delivery to the islet [6].”
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Current advanced therapy cell-based medicinal products for type-1-diabetes treatment
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“Several recent studies have shown that islet hypoxia induces activation of HIF-1a as a result of deletion of the von Hippel–Lindau protein in beta cells resulting in impaired glucose-stimulated insulin secretion [14,15] and expression of pro-apoptotic genes [16,17].”
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“This suggests that the bile acid incorporation created a microenvironment where cell survival was greatly compromised resulting in deterioration of viability and functionality and reduced mitochondrial activity and cellular metabolism (Cantley et al., 2010).”
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“an important contributor to islet dysfunction with resultant apoptosis and necrosis [168, 169].”
BackgroundGenetic strategies to bring islet xenotransplantation to the clinic
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“The role of hypoxia in ß-cell formation and function has recently gained considerable interest [1].”
BackgroundSweet and Sour β-Cells: ROS and Hif1α Induce Warburg-Like Lactate Production During Type 2 Diabetes
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“So what is the ROS-dependent mechanism driving the lactate shunt and b-cell dysfunction? Activation of Hif1a is known to increase the expression of Ldha and other genes involved in glycolytic lactate production (11) and, moreover, has been shown to disrupt glucose sensing and GSIS in b-cells (12–15), as reviewed previ…”
BackgroundSelf-citationClinical islet transplantation
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“Suppression of β-cell metabolism may protect against longer bouts of hypoxia or stress. β-cells are susceptible to hypoxia because they rely on quantitative production of ATP by oxidative metabolism to secrete insulin (Cantley et al 2010).”
BackgroundImproving cellular fitness of human stem cell-derived islets under hypoxia
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 13 · see citing works
“Thesefactorscanultimatelycontributetoisletcelldeath 16,31 . β cells that survive in hypoxic conditions undergo a metabolic shift from aerobic glucose metabolism to anaerobic glycolysis, resulting in impaired functional capabilities 32,33 .”
Fluorescence lifetime metabolic mapping of hypoxia‐induced damage in pancreatic pseudo‐islets
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Conditional islet hypovascularisation does not preclude beta cell expansion during pregnancy in mice
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Hyperoxia reverses glucotoxicity-induced inhibition of insulin secretion in rat INS-1 β cells
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Characteristics of obstructive sleep apnea related to insulin resistance
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“In this context, some research focuses on the regulation of hypoxia-inducible factor 1 (HIF-1), a protein complex that enhances the expression of specific genes in response to low oxygen levels [25].”
Formulation strategies to provide oxygen-release to contrast local hypoxia for transplanted islets
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“HIF is expressed in pancreatic b-cells as well [9,31,32], but why the HIMP1 protein is not normally expressed in mouse Figure 3.”
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Pancreatic Islet Viability Assessment Using Hyperspectral Imaging of Autofluorescence
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“This is because the decreased production of ATP from glycolysis relative to oxidative phosphorylation cripples glucose-triggered insulin secretion, rendering islets non-responsive to fluctuating glucose in the external milieu [11,49].”
Self-citationHals, I. K., Ohki, T., Singh, R., Ma, Z.-H., Björklund, A., Balasuriya, C., Scholz, H., & Grill, V. (2017) · Physiological Reports · doi:10.14814/phy2.13447 · Cited by 8
“Negative effects of hypoxia are well recognized and studied (Dionne et al. 1993; Cantley et al. 2010), however, those of hyperoxia are less so and their clinical importance have not been much elucidated. ª 2017 The Authors.”
BackgroundPancreatic 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).”
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“While previous reviews have addressed β -cell responses to hypoxia [16] and the role of HIF signaling in β -cell function [17], this review provides several distinct contributions.”
Advances in oxygen-releasing matrices for regenerative engineering applications
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Metabolic Stress Impairs Pericyte Response to Optogenetic Stimulation in Pancreatic Islets
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“However, there was an increased expression of hypoxia-responsive genes in islets, such as Hif1a and Glut1 (Slc2a1) (45) (Figure 2C).”
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“28,29 Interestingly, hypoxia and cell-ECM detachment trigger similar molecular mechanisms: in a dialog of activation and inhibition of regulators such as the MAPK cascade, p38, JNK, and ERK, both processes lead to the induction of cytokine secretion, which in turn intensifies death mechanisms, as…”
BackgroundTherapeutic Effects of a Non-Beta Cell Bioartificial Pancreas in Diabetic Mice
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“Although these findings relate to A-cells, L-cells also rely on glucose metabolism for stimulated secretion (24) which is disrupted under hypoxic conditions (25).”
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“As discussed in the upper sections, the presence of sufficient oxygen is vital to prevent the activation of NF κ B and HIF-1 α , which impairs glucose uptake and glucose sensing, thereby disturbing the physiological glucose-stimulated insulin responsiveness [32,33,71].”
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“Islet isolation and cultivation as well as hypoxic conditions after transplantation can induce endoplasmic reticulum (ER) stress and ROS formation that reduces beta cell viability [31,32].”
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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).”
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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.
- 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 › Surgery › 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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