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Deletion of the von Hippel–Lindau gene in pancreatic β cells impairs glucose homeostasis in mice
Open accessAbstract
Defective insulin secretion in response to glucose is an important component of the beta cell dysfunction seen in type 2 diabetes. As mitochondrial oxidative phosphorylation plays a key role in glucose-stimulated insulin secretion (GSIS), oxygen-sensing pathways may modulate insulin release. The von Hippel-Lindau (VHL) protein controls the degradation of hypoxia-inducible factor (HIF) to coordinate cellular and organismal responses to altered oxygenation. To determine the role of this pathway in controlling glucose-stimulated insulin release from pancreatic beta cells, we generated mice lacking Vhl in pancreatic beta cells (betaVhlKO mice) and mice lacking Vhl in the pancreas (PVhlKO mice). Both mouse strains developed glucose intolerance with impaired insulin secretion. Furthermore, deletion of Vhl in beta cells or the pancreas altered expression of genes involved in beta cell function, including those involved in glucose transport and glycolysis, and isolated betaVhlKO and PVhlKO islets displayed impaired glucose uptake and defective glucose metabolism. The abnormal glucose homeostasis was dependent on upregulation of Hif-1alpha expression, and deletion of Hif1a in Vhl-deficient beta cells restored GSIS. Consistent with this, expression of activated Hif-1alpha in a mouse beta cell line impaired GSIS. These data suggest that VHL/HIF oxygen-sensing mechanisms play a critical role in glucose homeostasis and that activation of this pathway in response to decreased islet oxygenation may contribute to beta cell dysfunction.
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“In pancreatic β cells, excessive HIF-1α signaling - driven by hypoxia, glucotoxicity, or oxidative stress - impairs mitochondrial metabolism and ATP production, thereby compromising glucose stimulated insulin secretion [[238], [239], [240]].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [238]
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Cited by
Sorted by citations
Items 101–130 of 130
Relation of Hypoxia Inducible Factor, Dyslipidemia and CAD Saudi Patients With Type 2 Diabetes
Gharib, A. F., Saber, T., Askary, A. E., Alharthi, A., ALSALMI, N. A., ALHASHMI, S. T., AL-ASIRI, R. F., & Shafie, A. (2022) · In Vivo · doi:10.21873/invivo.12984 · Cited by 6
The hypoxia response and nutritional peptides
Kietzmann, T., & Mäkelä, V. H. (2021) · Peptides · doi:10.1016/j.peptides.2021.170507 · Cited by 8
“This makes pancreatic beta-cells sensible to hypoxia and several lines of evidence indicated that acute, chronic and intermittent hypoxia via the HIF pathway are important for beta cell function and pancreas development [20,26,71,118,129].”
BackgroundOverexpression of HIF-2α in pancreatic β cells does not alter glucose homeostasis
Brunt, J. J., Shi, S. Y., Schroer, S. A., Sivasubramaniyam, T., Cai, E. P., & Woo, M. (2014) · Islets · doi:10.1080/19382014.2015.1006075 · Cited by 8
Chen, Y., Zhou, Y., Wei, X., Yang, Y., Li, X.-J., Xu, Y.-J., Liu, C., & Chen, Z.-Y. (2021) · Toxicon · doi:10.1016/j.toxicon.2021.08.017 · Cited by 7
Qi, X.-P., Liu, W.-T., Li, J.-Y., Dai, Y.-J., Ma, J.-M., Zhao, Y., Fei, J., Li, F., Shen, M., Jin, H.-Y., et al. (2013) · Molecular Medicine Reports · doi:10.3892/mmr.2013.1578 · Cited by 7
“3) that is widely expressed in fetal and adult tissues (11,12).”
BackgroundAkram, J., Menezes, P., Idris, N. I., Thomas, J. E., Darwish, R., Tania, A., Butler, A. E., & Moin, A. S. M. (2025) · Cells · doi:10.3390/cells14242014 · Cited by 9
“…the therapeutic application of HIF pathway modulators requires careful titration, as excessive or prolonged HIF-1 α activation can paradoxically impair β -cell function by shifting cellular metabolism excessively toward glycolysis and reducing glucose-stimulated insulin secretion [23,175,176].”
Ku, Y., Ahn, C. H., Jung, C.-H., Lee, J., Kim, L.-K., Kwak, S., Jung, H., Park, K., & Cho, Y. (2013) · Endocrinology and Metabolism · doi:10.3803/enm.2013.28.4.320 · Cited by 6
Regulating islet stress responses through CD47 activation
Kale, A., Azar, M., Cheng, V., Robertson, H., Coulter, S., Mehta, P. M., Julovi, S., Patrick, E., Ghimire, K., & Rogers, N. M. (2025) · Diabetologia · doi:10.1007/s00125-025-06409-3 · Cited by 5
“Changes in transcriptional profiles in hypoxic islets are coordinated by HIF, and studies demonstrate that HIF1α activation impairs beta cell function (and consequent glucose control) by switching glucose metabolism from aerobic oxidative phosphorylation to anaerobic glycolysis [35, 36].”
Kato, H., Salgado, M., Mendez, D., Gonzalez, N., Rawson, J., Ligot, D., Balandran, B., Orr, C., Quijano, J. C., Omori, K., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-61604-3 · Cited by 5
“In fact, it was reported that the loss of VHL induced impaired β-cell function and mass via HIF1A upregulation 48,49 .”
Identifying HIF Activity in Three-Dimensional Cultures of Islet-Like Clusters
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Cell-based therapy of diabetes: what are the new sources of beta cells?
Soggia, A., Hoarau, E., Bechetoille, C., Simon, M., Heinis, M., & Duvillié, B. (2011) · Diabetes & Metabolism · doi:10.1016/j.diabet.2011.05.007 · Cited by 4
HIF inhibition: Current strategies and clinical challenges
Więch-Walów, A., Bartoszewska, S., Barton, A., Czechowicz, P., Dudzik, J., Wielockx, B., Collawn, J. F., & Bartoszewski, R. (2026) · Redox biology · doi:10.1016/j.redox.2026.104220 · Cited by 3
“In pancreatic β cells, excessive HIF-1 α signaling - driven by hypoxia, glucotoxicity, or oxidative stress - impairs mitochondrial metabolism and ATP production, thereby compromising glucose stimulated insulin secretion [238 – 240].”
Stabilization of HIF-2α impacts pancreas growth
Flores‐Martínez, Á., García-Núñez, A., Rojas, A., & Cano, D. A. (2018) · Scientific Reports · doi:10.1038/s41598-018-32054-5 · Cited by 5
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Wang, T., Wei, W., Mansai, H., Huang, C., Li, L., Ye, Q., Yin, H., Yang, C., Li, X.-J., Liu, S.-H., et al. (2018) · Molecular Medicine Reports · doi:10.3892/mmr.2018.8759 · Cited by 3
Early postnatal activation of the hypoxia pathway disrupts β-cell functionPreprint
Yang, J., Hammoud, B., Ridler, A., Won, K., Hoshi, T., Stanley, C. A., Stanescu, D. E., & Ackermann, A. M. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.06.09.447705 · Cited by 4
“Loss of VHL in differentiated β-cells leads to a normal or slightly lower plasma glucose and a mild impairment in glucose tolerance (13-16).”
BackgroundDiaz-Herreros, A. N., Granados-Galeana, A., Martínez-Torres, I., Reyes-Maldonado, E., Rosales-Cruz, E., Gómez-Chávez, F., Betanzos-Cabrera, G., Valdez-Guerrero, A., Cancino-Diaz, J. C., & Cancino-Diaz, M. E. (2025) · Diabetology · doi:10.3390/diabetology6120143 · Cited by 1
Halperin, R., Horwitz, R., Schwarz, Y., & Tirosh, A. (2025) · Cardiovascular Diabetology · doi:10.1186/s12933-025-02799-1 · Cited by 1
“Inducing a conditional deletion of VHL in mice pancreatic beta cells results in altered gene expression, reduced islet cell cytoplasmic stimulation by glucose and diminished insulin secretion [26, 27], with deletion of Hif1a restoring glucose homeostasis [28].”
High glucose-induced ubiquitylation of G6PD leads to the injury of podocytePreprint
Wang, M., Hu, J., Yan, L.-L., Yang, Y.-P., He, M., Guo, S.-Z., Wu, M., Li, Q., Gong, W., Yang, Y., et al. (2018) · bioRxiv · doi:10.1101/350694 · Cited by 1
“indicating that VHL may participate in the pathogenesis of diabetes[48-50].”
BackgroundThe role of Npas4 and Rgs2 in the regulation of pancreatic β-cell function
Speckmann, T. (2019) · doi:10.14288/1.0380061 · Cited by 1
“Chronically elevated HIF1α signalling is detrimental to β-cell function, identity and viability [497; 519-521; 838].”
BackgroundSaranaruk, P., Sato, Y., Tsuruta, M., & Yamagata, K. (2026) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2026.154627
Su, Y., Chen, Y., Yang, H., Liang, Q., Luo, T., Leng, Y., Zhang, J., Zheng, T., Xie, C., & Fu, X. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1879557
Diaz-Herreros, A. N., Reyes‐Maldonado, E., Rosales-Cruz, É., Gómez‐Chávez, F., Valdez-Guerrero, A. S., Rodríguez‐Cortés, O., Cancino‐Díaz, J. C., & Cancino-Diaz, M. E. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27104640
“Similar findings were described by Cantley et al. in 2009 [12] and Choi et al. in 2011 [13], who also found a significant reduction in GLUT-2 and that high GLUT-1 expression is regulated by HIF-1 α .”
Gang, N., van Allen, K. A., Willmore, W. G., Lynn, F. C., & Bruin, J. E. (2025) · Islets · doi:10.1080/19382014.2025.2526871 · Cited by 3
Левчук, Н. І., Kovzun, О. I., & Tronko, M. D. (2024) · Актуальні проблеми сучасної медицини Вісник Української медичної стоматологічної академії · doi:10.31718/2077-1096.24.4.323
“Порушення сигналізації HIF-1α при-зводить до дисфункції β-клітин під-шлункової залози та розвитку ЦД 2 типу [8,9].”
Gang, N., van Allen, K. A., Willmore, W. G., Lynn, F. C., & Bruin, J. E. (2024) · bioRxiv · doi:10.1101/2024.09.25.615065
Editorial: Hypoxia, oxidative stress, and endocrine cancers
Duvillié, B., & Jockers, R. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1268268
Hypoxia causes pancreatic β-cell dysfunction by activating a transcriptional repressor BHLHE40Preprint
Tsuyama, T., Sato, Y., Yoshizawa, T., Matsuoka, T.-A., & Yamagata, K. (2022) · bioRxiv · doi:10.1101/2022.06.28.498031
“However, hyperactivation of 73 HIF in β-cells impairs insulin secretion by switching glucose metabolism from aerobic 74 oxidative phosphorylation to anaerobic glycolysis (14-16), suggesting that activation of 75 HIF underlies β-cell dysfunction and glucose intolerance in hypoxia.”
BackgroundThe prolyl hydroxylase PHD3 maintains β-cell glucose metabolism during fatty acid excessPreprint
Nasteska, D., Cuozzo, F., Thakker, A., Bakar, R. B., Westbrook, R. L., Akerman, I., Cantley, J., Tennant, D., & Hodson, D. (2020) · bioRxiv · doi:10.1101/2020.04.30.068106
Self-citationCélula beta, diabetes y la ruta de hypoxia inducible factor
Cano, D. A. (2013) · Avances en Diabetología · doi:10.1016/j.avdiab.2013.01.004
Pillai, R., & Jamie, W. (2012) · InTech eBooks · doi:10.5772/34095
“…published from independent laboratories studying the impact of increasing HIF-1┙ levels in beta-cells indicate that one has to be extremely cautious when using pharmacological agents, such as DFS, to activate HIF-1┙ in the islets (Puri et al., 2008; Zehetner et al., 2008; Cantley et al., 2009).”
Background
Metadata
- Authors
- Cantley, J., Selman, C., Shukla, D., Abramov, A. Y., Forstreuter, F., Esteban, M. A., Claret, M., Lingard, S. J., Clements, M., Harten, S. K., Asare-Anane, H., Batterham, R. L., Herrera, P. L., Persaud, S. J., Duchen, M. R., Maxwell, P. H., & Withers, D. J.
- Affiliations
- University College London (GB)
- University of Geneva (CH)
- King's College London (GB)
- Garvan Institute of Medical Research (AU)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2008-12-08
- Volume
- 119
- Issue
- 1
- Pages
- 125-35
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2613475
- OpenAlex
- W2149635697
- Cited by
- 127
- References
- 0
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 7 · 2023: 2 · 2022: 10 · 2021: 5 · 2020: 5 · 2019: 3 · 2018: 7 · 2017: 7 · 2016: 4 · 2015: 6 · 2014: 12 · 2013: 17 · 2012: 18
- FWCI
- 7.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Wellcome Trust
- Cancer Research UK
- British Heart Foundation
- Diabetes UK
- European Commission
- Directorate for Biological Sciences
- University of California, San Diego
- Medical Research Council
- Biotechnology and Biological Sciences Research Council
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- von Hippel-Lindau protein, pancreatic beta cells, glucose-stimulated insulin secretion, glucose homeostasis, hypoxia-inducible factor-1α, oxygen sensing, beta-cell dysfunction, type 2 diabetes, glucose uptake, glycolysis, mitochondrial oxidative phosphorylation, impaired glucose tolerance
- MeSH terms
- Animals, Glucose, Homeostasis, Insulin, Mice, Inbred C57BL, Oxygen, Mice, Knockout, Insulin-Secreting Cells, Glucose Transporter Type 1, Glucose Transporter Type 2, Mice, Von Hippel-Lindau Tumor Suppressor Protein
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