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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In pancreatic β cells, excessive HIF-1α signaling driven by hypoxia, glucotoxicity, or oxidative stress impairs mitochondrial metabolism and ATP production, compromising glucose-stimulated insulin secretion.
“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]
The Results report altered glucose-responsive metabolism in Vhl-deficient mouse β cells, and the Discussion links HIF-1α activation to disrupted coupling between oxidative phosphorylation and glucose-stimulated insulin secretion (GSIS); it also suggests hypoxia could activate this pathway. The paper does not establish glucotoxicity or oxidative stress as triggers here, or directly show reduced ATP production; it describes reduced coupling to mitochondrial ATP production as an expectation. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Jaakkola, P., Mole, D. R., Tian, Y.-M., Wilson, M. I., Gielbert, J., Gaskell, S. J., Kriegsheim, A. V., Hebestreit, H. F., Mukherji, M., Schofield, C. J., et al. (2001) · Science · doi:10.1126/science.1059796 · Cited by 5,535 · see citing works
Self-citationRegulation of Mammalian O <sub>2</sub> Homeostasis by Hypoxia-Inducible Factor 1
Semenza, G. L. (1999) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.15.1.551 · Cited by 1,914 · see citing works
NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α
Rius, J., Guma, M., Schachtrup, C., Akassoglou, K., Zinkernagel, A. S., Nizet, V., Johnson, R. S., Haddad, G. G., & Karin, M. (2008) · Nature · doi:10.1038/nature06905 · Cited by 1,614 · see citing works
Hypoxia requires Notch signaling to maintain the undifferentiated cell state
Gustafsson, M. V., Zheng, X., Pereira, T., Gradin, K., Jin, S., Lundkvist, J., Ruas, J. L., Poellinger, L., Lendahl, U., & Bondesson, M. (2005) · Developmental Cell · doi:10.1016/j.devcel.2005.09.010 · Cited by 1,109 · see citing works
Diabetes mellitus and genetically programmed defects in β-cell function
Bell, G. I., & Polonsky, K. S. (2001) · Nature · doi:10.1038/414788a · Cited by 475 · see citing works
Proline hydroxylation and gene expression
Kaelin, W. G. (2005) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.74.082803.133142 · Cited by 468 · see citing works
Regulation of E-cadherin Expression by <i>VHL</i> and Hypoxia-Inducible Factor
Esteban, M. A., Tran, M. G. B., Harten, S. K., Hill, P., Castellanos, M. C., Chandra, A., Raval, R., O'Brien, T. S., & Maxwell, P. H. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-2670 · Cited by 262 · see citing works
Self-citationLoss of Skeletal Muscle HIF-1α Results in Altered Exercise Endurance
Mason, S. D., Howlett, R. A., Kim, M. J., Olfert, I. M., Hogan, M. C., McNulty, W., Hickey, R. P., Wagner, P. D., Kahn, C. R., Giordano, F. J., et al. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020288 · Cited by 210 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Haase, V.H., Glickman, J.N., Socolovsky, M., and Jaenisch, R. 2001. Vascular tumors in livers with targeted inactivation of the von Hippel-Lindau tumor suppressor. Proc. Natl. Acad. Sci. U. S. A. 98:1583-1588.
Cited by
Sorted by citations
Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men
Rorsman, P., & Ashcroft, F. M. (2018) · Physiological Reviews · doi:10.1152/physrev.00008.2017 · Cited by 793 · see citing works
Regulation of erythropoiesis by hypoxia-inducible factors
Haase, V. H. (2013) · Blood Reviews · doi:10.1016/j.blre.2012.12.003 · Cited by 787 · see citing works
The Role of Oxidative Stress and Hypoxia in Pancreatic Beta-Cell Dysfunction in Diabetes Mellitus
Gerber, P. A., & Rutter, G. A. (2017) · Antioxidants & Redox Signaling · doi:10.1089/ars.2016.6755 · Cited by 654 · see citing works
“This modification leads to oxygen concentration-independent stabilization of HIFs (25, 153, 210).”
InfluentialHypoxia and hypoxia-inducible factors in diabetes and its complications
Catrina, S.-B., & Zheng, X. (2021) · Diabetologia · doi:10.1007/s00125-021-05380-z · Cited by 400 · see citing works
The role of hypoxia-inducible factors in metabolic diseases
Gonzalez, F., Xie, C., & Jiang, C.-T. (2018) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0096-z · Cited by 376 · see citing works
Pancreatic β-cell identity, glucose sensing and the control of insulin secretion.
Rutter, G., Pullen, T., Hodson, D., & Martinez-Sánchez, A. (2015) · Biochemical Journal · doi:10.1042/bj20141384 · Cited by 344 · see citing works
Bensellam, M., Laybutt, D., & Jonas, J. (2012) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2012.08.003 · Cited by 282 · see citing works
“…for β-cells as revealed by the phenotypical alterations observed in mice lacking vhl (Cantley et al., 2009; Choi et al., 2011; Puri et al., 2009; Zehetner et al., 2008), Arnt (Gunton et al., 2005), and Hif1α (Cheng et al., 2010), although the latter is controversial (Cantley et al., 2009).”
BackgroundInfluentialHypoxia-inducible factor-1α regulates β cell function in mouse and human islets
Cheng, K., Ho, K., Stokes, R., Scott, C., Lau, S. M., Hawthorne, W. J., O’Connell, P. J., Loudovaris, T., Kay, T. W., Kulkarni, R. N., et al. (2010) · Journal of Clinical Investigation · doi:10.1172/jci35846 · Cited by 230 · see citing works
Regulation of human metabolism by hypoxia-inducible factor
Formenti, F., Constantin-Teodosiu, D., Emmanuel, Y., Cheeseman, J., Dorrington, K., Edwards, L., Humphreys, S., Lappin, T., McMullin, M., McNamara, C. J., et al. (2010) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1002339107 · Cited by 172 · see citing works
Hypoxia-inducible factors and diabetes
Gunton, J. E. (2020) · Journal of Clinical Investigation · doi:10.1172/jci137556 · Cited by 159 · see citing works
Richards, O. C., Raines, S. M., & Attie, A. (2010) · Endocrine Reviews · doi:10.1210/er.2009-0035 · Cited by 141 · see citing works
“metabolism, and insulin secretion (37).”
Sato, Y., Endo, H., Okuyama, H., Takeda, T., Iwahashi, H., Imagawa, A., Yamagata, K., Shimomura, I., & Inoue, M. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.194738 · Cited by 145 · see citing works
Hypoxia-inducible factors and obstructive sleep apnea
Prabhakar, N. R., Peng, Y., & Nanduri, J. (2020) · Journal of Clinical Investigation · doi:10.1172/jci137560 · Cited by 319 · see citing works
Metabolism, hypoxia and the diabetic heart
Heather, L. C., & Clarke, K. (2011) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2011.01.007 · Cited by 131 · see citing works
The hypoxia response pathway and <i>β</i> ‐cell function
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 · Cited by 119 · see citing works
“However, data recently published by us and others [9–11] clearly show that Hif1α protein is not stabilized in the β-cells of normal wild-type mice and that deletion of Hif1α does not alter glucose homeostasis or GSIS [9,11] questioning the role of Hif1α under normal physiological conditions.”
BackgroundResultInfluentialSelf-citationHuang, Y., Lei, L., Liu, D., Jovin, I., Russell, R., Johnson, R., Lorenzo, A. D., & Giordano, F. J. (2012) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1209281109 · Cited by 111 · see citing works
“Interestingly, the HIF pathway is involved substantively in pancreatic β-cell function, but the effects on glucose homeostasis and insulin secretion are the inverse of those we show in EC–HIF-1α mice (30).”
BackgroundOxygen Tension Regulates Pancreatic β-Cell Differentiation Through Hypoxia-Inducible Factor 1α
Heinis, M., Simon, M., Ilc, K., Mazure, N. M., Pouysségur, J., Scharfmann, R., & Duvillié, B. (2009) · Diabetes · doi:10.2337/db09-0891 · Cited by 112 · see citing works
“(37) used Pdx1-CRE recombinase to delete VHL in pancreatic progenitors.”
MethodResultInfluentialReinert, R. B., Brissova, M., Shostak, A., Pan, F. C., Poffenberger, G., Cai, Q., Hundemer, G. L., Kantz, J., Thompson, C., Dai, C., et al. (2013) · Diabetes · doi:10.2337/db13-0071 · Cited by 98 · see citing works
Bensellam, M., Duvillié, B., Rybachuk, G., Laybutt, D., Magnan, C., Guiot, Y., Pouysségur, J., & Jonas, J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0029807 · Cited by 92 · see citing works
Systemic VHL gene functions and the VHL disease
Bader, H. L., & Hsu, T. (2012) · FEBS Letters · doi:10.1016/j.febslet.2012.04.032 · Cited by 79 · see citing works
Cai, Q., Briššová, M., Reinert, R. B., Pan, F. C., Brahmachary, P. P., Jeansson, M., Shostak, A., Aramandla, R., Poffenberger, G., Quaggin, S. E., et al. (2012) · Developmental Biology · doi:10.1016/j.ydbio.2012.04.022 · Cited by 83 · see citing works
“Oxygen is important for normal β cell development and function, with hypoxia leading to decreased insulin content and islet formation (Cantley et al., 2009; Cheng et al., Dev Biol.”
BackgroundNovel links between HIFs, type 2 diabetes, and metabolic syndrome.
Girgis, C., Cheng, K., Scott, C. H., & Gunton, J. (2012) · Trends in endocrinology and metabolism · doi:10.1016/j.tem.2012.05.003 · Cited by 76 · see citing works
Mao, Z., Xia, W., Chang, H., Huo, W., Li, Y., & Xu, S. (2015) · Toxicology Letters · doi:10.1016/j.toxlet.2015.08.009 · Cited by 82 · see citing works
Puri, S., Akiyama, H., & Hebrok, M. (2013) · Genes & Development · doi:10.1101/gad.227785.113 · Cited by 73 · see citing works
Jiang, C.-T., Kim, J.-H., Li, F., Qu, A.-J., Gavrilova, O., Shah, Y., & Gonzalez, F. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.426338 · Cited by 73 · see citing works
“Third, three independent laboratories demonstrated that increased HIF1 levels impair -cell function and glucose homeostasis (24, 25, 50), which is paradoxical to the results from the DFS study.”
ResultHIF prolyl hydroxylase inhibitors for anemia
Muchnik, E., & Kaplan, J. (2011) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2011.566861 · Cited by 76 · see citing works
“Mouse studies have shown that deletion of the VHL gene in either the islet cells or entire pancreas of mice caused glucose intolerance with impaired insulin secretion; this was blocked by elimination of HIF-1a [111].”
BackgroundImpact of the Hypoxia-Inducible Factor-1 α (HIF1A) Pro582Ser Polymorphism on Diabetes Nephropathy
Gu, H., Zheng, X., Seman, N. A., Gu, T., Botusan, I., Sunkari, V., Lokman, E. F., Brismar, K., & Catrina, S. (2013) · Diabetes Care · doi:10.2337/dc12-1125 · Cited by 72 · see citing works
mTOR links incretin signaling to HIF induction in pancreatic beta cells
Velde, S. S. V. D., Hogan, M. F., & Montminy, M. (2011) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1114228108 · Cited by 72 · see citing works
“The degree of HIF activation appears critical, however; unbridled HIF induction in mice with a knockout of the E3 ligase Von Hippel-Lindau (VHL) leads to persistent defects in glucose-stimulated insulin secretion (26).”
Role of Reactive Oxygen Species in Glucose Metabolism Disorder in Diabetic Pancreatic β-Cells
Mukai, E., Fujimoto, S., & Inagaki, N. (2022) · Biomolecules · doi:10.3390/biom12091228 · Cited by 73 · see citing works
The impact of acute caloric restriction on the metabolic phenotype in male C57BL/6 and DBA/2 mice.
Hempenstall, S., Picchio, L., Mitchell, S., Speakman, J., & Selman, C. (2010) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2009.12.008 · Cited by 68 · see citing works
“…h) after 1 week and 4 weeks of 30% CR. Mice were weighed, injected intraperitoneally (IP) witH 20% D-glucose (2 g kg 1) and blood glucose levels, collected from tail vein samples, were determined using a glucometer (OneTouch Ultra, Lifescan, UK) as previously described (Cantley et al., 2009).”
MethodSelf-citationHIF-1α inhibitor PX-478 preserves pancreatic β cell function in diabetes
Ilegems, E., Bryzgalova, G., Correia, J., Yesildag, B., Berra, E., Ruas, J., Pereira, T., & Berggren, P. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.aba9112 · Cited by 67 · see citing works
Zhao, Y., Xue, Q., Su, X., Xie, L.-Q., Yan, Y.-J., Wang, L.-X., & Steinman, A. (2016) · Environmental Science and Technology · doi:10.1021/acs.est.5b03369 · Cited by 67
Fumarate Hydratase Deletion in Pancreatic β Cells Leads to Progressive Diabetes
Adam, J., Ramracheya, R. D., Chibalina, M. V., Ternette, N., Hamilton, A., Tarasov, A. I., Zhang, Q., Rebelato, E., Rorsman, N. J. G., Martín-del-Río, R., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.08.093 · Cited by 60 · see citing works
Cantley, J. (2014) · Mammalian Genome · doi:10.1007/s00335-014-9538-7 · Cited by 67 · see citing works
“2010, 2013) and hypoxia-inducible factor 1a activation (Cantley et al. 2009); therefore, as nutrient stimulation can lead to a transient decrease in oxygen tension (Bensellam et al.”
BackgroundSelf-citationBeall, C., Piipari, K., Al‐Qassab, H., Smith, M. A., Parker, N., Carling, D., Viollet, B., Withers, D., & Ashford, M. (2010) · Biochemical Journal · doi:10.1042/bj20100231 · Cited by 64 · see citing works
Self-citationModerate Hypoxia Induces β-Cell Dysfunction with HIF-1–Independent Gene Expression Changes
Sato, Y., Inoue, M., Yoshizawa, T., & Yamagata, K. (2014) · PLoS ONE · doi:10.1371/journal.pone.0114868 · Cited by 60 · see citing works
Impaired hypoxia-inducible factor (HIF) regulation by hyperglycemia
Catrina, S. (2014) · Journal of molecular medicine · doi:10.1007/s00109-014-1166-x · Cited by 60 · see citing works
“A similar glucose handling disturbance was observed in other knockout models [55, 53], which suggests a deleterious effect of excessive HIF-1α activation on glucose-dependent insulin secretion [53].”
Adipocyte Pseudohypoxia Suppresses Lipolysis and Facilitates Benign Adipose Tissue Expansion
Michailidou, Z., Morton, N., Moreno-Navarrete, J., West, C., Stewart, K., Fernández-Real, J., Schofield, C., Seckl, J., & Ratcliffe, P. (2014) · Diabetes · doi:10.2337/db14-0233 · Cited by 58 · see citing works
Pancreatic cyst development: insights from von Hippel-Lindau disease
van Asselt, S. V., de Vries, E. D., van Dullemen, H., Brouwers, A., Walenkamp, A., Giles, R., & Links, T. (2013) · Cilia · doi:10.1186/2046-2530-2-3 · Cited by 55
“However, others did find increased vascularization in islets in conditional Vhlh knock-out mice in β-cells [73-75].”
BackgroundA Preexistent Hypoxic Gene Signature Predicts Impaired Islet Graft Function and Glucose Homeostasis
Cantley, J., Walters, S., Jung, M.-H., Weinberg, A., Cowley, M., Whitworth, P. T., Kaplan, W., Hawthorne, W., O'Connell, P., Weir, G., et al. (2013) · Cell Transplantation · doi:10.3727/096368912x658728 · Cited by 54 · see citing works
Self-citationMitochondria mediated cell death in diabetes
Szabadkai, G., & Duchen, M. R. (2009) · APOPTOSIS · doi:10.1007/s10495-009-0363-5 · Cited by 52 · see citing works
“Bad-/- b-cells exhibit a higher rate of proliferation due to impaired cell death, but the presence of Bad is also necessary for GK function, thus for GSIS of the b-cell [132].”
BackgroundInfluentialSelf-citationCantley, J., Burchfield, J. G., Pearson, G. L., Schmitz‐Peiffer, C., Leitges, M., & Biden, T. J. (2009) · Diabetes · doi:10.2337/db09-0132 · Cited by 53 · see citing works
Self-citationMansor, L. S., Mehta, K., Aksentijević, D., Carr, C. A., Lund, T., Cole, M. A., Page, L. M. L., Fialho, M. D. L. S., Shattock, M. J., Aasum, E., et al. (2015) · The Journal of Physiology · doi:10.1113/jp271242 · Cited by 55 · see citing works
Macías, D., Fernández-Agüera, M. C., Bonilla-Henao, V., & López-Barneo, J. (2014) · EMBO Molecular Medicine · doi:10.15252/emmm.201404153 · Cited by 51 · see citing works
“In agreement with these findings, homozygous Vhl deletion has been shown to produce impairment of pancreatic beta cell function (Cantley et al , 2009) and apoptosis in thymocytes and chondrocytes (Haase, 2005).”
McClain, D., Abuelgasim, K., Nouraie, M., Salomon-Andonie, J., Niu, X.-M., Miasnikova, G. Y., Polyakova, L. A., Sergueeva, A. I., Okhotin, D. J., Cherqaoui, R., et al. (2012) · Journal of molecular medicine · doi:10.1007/s00109-012-0961-5 · Cited by 49 · see citing works
“When glucose challenged, however, the mice with homozygous deletion of VHL exhibit impaired glucose-stimulated insulin secretion because of decreased rates of glucose oxidation [19, 22, 25].”
mTOR: A double-edged sword for diabetes
Tuo, Y., & Xiang, M. (2018) · Journal of Leukocyte Biology · doi:10.1002/jlb.3mr0317-095rr · Cited by 50 · see citing works
Hyperinsulinism and Diabetes: Genetic Dissection of β Cell Metabolism-Excitation Coupling in Mice
Remedi, M. S., & Nichols, C. G. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.10.011 · Cited by 39 · see citing works
Jeelani, I., Moon, J.-S., da Cunha, F. F., Nasamran, C., Jeon, S., Zhang, X.-H., Bandyopadhyay, G. K., Dobaczewska, K., Mikulski, Z., Hosseini, M., et al. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.adi0284 · Cited by 46 · see citing works
Peiris, H., Raghupathi, R., Jessup, C., Zanin, M. P., Mohanasundaram, D., Mackenzie, K. D., Chataway, T., Clarke, J., Brealey, J., Coates, P., et al. (2012) · Endocrinology · doi:10.1210/en.2011-2149 · Cited by 46 · see citing works
“Blood insulin levels were measured after 16 h fasting using an ultrasensitive mouse insulin ELISA kit (Crystal Chem Downers Grove, IL) according to the manufacturer’s instructions for a low-range assay (17) Absorbance was measured at 450 and 620 nm using a BIOMECK-3000 microplate reader (BeckmanCoulter Brea, CA) and M…”
MethodSasaki, M., Fujimoto, S., Sato, Y., Nishi, Y., Mukai, E., Yamano, G., Sato, H., Tahara, Y., Ogura, K., Nagashima, K., et al. (2013) · Diabetes · doi:10.2337/db12-0903 · Cited by 38 · see citing works
“HIF1a downregulates the expression of GLUT2 and glucokinase and upregulates PDK-1, which inactivates pyruvate dehydrogenase and suppresses metabolism in the Krebs cycle (44) in islets of von Hippel-Lindau gene (vhl)deficient mice (45).”
BackgroundCrosstalk between the developing pancreas and its blood vessels: an evolving dialogue
Villasenõr, A., & Cleaver, O. (2012) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2012.06.003 · Cited by 37
High glucose–induced ubiquitination of G6PD leads to the injury of podocytes
Wang, M., Hu, J., Yan, L., Yang, Y.-P., He, M., Wu, M., Li, Q., Gong, W., Yang, Y., Wang, Y., et al. (2019) · The FASEB Journal · doi:10.1096/fj.201801921r · Cited by 36 · see citing works
Cantley, J., Davenport, A., Vetterli, L., Nemes, N., Whitworth, P. T., Boslem, E., Thai, L. M., Mellett, N., Meikle, P., Hoehn, K. L., et al. (2018) · Diabetologia · doi:10.1007/s00125-018-4743-7 · Cited by 35
“1b), consistent with the >95% beta cell gene deletion efficiency reported for the INS2cre mouse [29] and the 75% beta cell content of mouse islets [30].”
ResultSelf-citationInhibition of aberrant Hif1α activation delays intervertebral disc degeneration in adult mice
Wang, Z.-Q., Chen, H.-G., Tan, Q.-Y., Huang, J.-L., Zhou, S., Luo, F.-T., Zhang, D., Yang, J., Li, C., Chen, B., et al. (2022) · Bone Research · doi:10.1038/s41413-021-00165-x · Cited by 33 · see citing works
“The VHL-HIF signaling pathway has multiple downstream target molecules implicated in the modulation of angiogenesis and cellular metabolism.(53) Most mammalian cells meet their energetic requirements mainly through mitochondrial oxidative phosphorylation in the presence of oxygen and rely on glycolysis in the cytosol…”
BackgroundCardiovascular adaptation to hypoxia and the role of peripheral resistance
Cowburn, A., Macías, D., Summers, C., Chilvers, E., & Johnson, R. (2017) · eLife · doi:10.7554/elife.28755 · Cited by 33 · see citing works
“Carotid body histology was performed as previously reported (Macı́as et al., 2014).”
MethodMicroenvironmental stimuli for proliferation of functional islet β-cells
Alismail, H., & Jin, S. (2014) · Cell & Bioscience · doi:10.1186/2045-3701-4-12 · Cited by 33 · see citing works
“VHL/HIF oxygen-sensing mechanisms play a critical role in glucose homeostasis through decreasing islet oxygenation level and negatively impact β-cell function [53,54].”
Backgroundβ-Klotho promotes glycolysis and glucose-stimulated insulin secretion via GP130
Geng, L., Liao, B., Jin, L., Yu, J., Zhao, X., Zhao, Y., Zhong, L., Wang, B., Li, J., Liu, J., et al. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00572-2 · Cited by 40 · see citing works
Uncovering the gene regulatory network of type 2 diabetes through multi-omic data integration
Liu, J., Liu, S., Yu, Z.-M., Qiu, X.-R., Jiang, R., & Li, W.-Z. (2022) · Journal of Translational Medicine · doi:10.1186/s12967-022-03826-5 · Cited by 31 · see citing works
“Hypoxia could activate the hypoxia-inducible factor rapidly, leading to the conversion of glucose utilization from aerobic to anaerobic metabolism, resulting in β-cell dysfunction [21, 22].”
Speckmann, T., Sabatini, P. V., Nian, C., Smith, R. G., & Lynn, F. C. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.704098 · Cited by 41 · see citing works
Evidence of a metabolic memory to early-life dietary restriction in male C57BL/6 mice
Selman, C., & Hempenstall, S. (2012) · Longevity & Healthspan · doi:10.1186/2046-2395-1-2 · Cited by 30 · see citing works
“In brief, mice were weighed, injected intraperitoneally with 20% D-glucose (2 g/kg) and then blood glucose levels were collected from tail vein samples and read on a glucometer (OneTouch Ultra, Lifescan, High Wycombe, UK) as previously described [46].”
MethodSelf-citationHypoxia-inducible factor-1 mediates pancreatic β-cell dysfunction by intermittent hypoxia
Wang, N., Shi, X., Khan, S. A., Wang, B. L., Semenza, G. L., Prabhakar, N. R., & Nanduri, J. (2020) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00309.2020 · Cited by 36 · see citing works
D'Hoker, J., Leu, N. D., Heremans, Y., Baeyens, L., Minami, K., Ying, C., Lavens, A., Chintinne, M., Stangé, G., Magenheim, J., et al. (2013) · Diabetes · doi:10.2337/db12-1827 · Cited by 29
Loss of Ahi1 Affects Early Development by Impairing BM88/Cend1-mediated Neuronal Differentiation
Weng, L., Lin, Y.-F., Li, A. L., Wang, C.-E., Yan, S., Sun, M., Gaertig, M., Mitha, N., Kosaka, J., Wakabayashi, T., et al. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.0119-13.2013 · Cited by 28 · see citing works
Different susceptibility of rat pancreatic alpha and beta cells to hypoxia
Bloch, K. O., Vennäng, J., Lazard, D., & Vardi, P. (2012) · Histochemistry and Cell Biology · doi:10.1007/s00418-012-0925-4 · Cited by 27 · see citing works
Tsuyama, T., Sato, Y., Yoshizawa, T., Matsuoka, T., & Yamagata, K. (2023) · EMBO Reports · doi:10.15252/embr.202256227 · Cited by 39 · see citing works
Deletion of myeloid IRS2 enhances adipose tissue sympathetic nerve function and limits obesity
Rached, M.-T., Millership, S. J., Pedroni, S. M. A., Choudhury, A. I., Costa, A. S. H., Hardy, D. G., Glegola, J. A., Irvine, E. E., Selman, C., Woodberry, M., et al. (2018) · Molecular Metabolism · doi:10.1016/j.molmet.2018.11.010 · Cited by 28 · see citing works
Self-citationBohuslavová, R., Čerychová, R., Nepomucka, K., & Pavlínková, G. (2017) · BMC Endocrine Disorders · doi:10.1186/s12902-017-0200-8 · Cited by 27 · see citing works
“HIF-1, by regulating the expression of glucose transporter GLUT1 and glycolytic enzymes, affects glucose homeostasis, including the regulation of glucose-stimulated insulin secretion (GSIS) from the pancreatic beta-cells [45].”
BackgroundSato, Y., Tsuyama, T., Sato, C., Karim, M., Yoshizawa, T., Inoue, M., & Yamagata, K. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.767574 · Cited by 27
Expression of Pro- and Antiapoptotic Molecules of the Bcl-2 Family in Human Islets Postisolation
Campbell, P., Weinberg, A., Chee, J., Mariana, L., Ayala, R., Hawthorne, W., O'Connell, P., Loudovaris, T., Cowley, M., Kay, T., et al. (2012) · Cell Transplantation · doi:10.3727/096368911x566262 · Cited by 26 · see citing works
HIF-1α serves as a co-linker between AD and T2DM
Yang, H. T., Ren, K., Zhang, Y., Yang, L., Cao, H., Yuan, X., Su, L., Li, H., Feng, X., & Liu, D. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116158 · Cited by 26 · see citing works
Liu, N., Cai, X., Liu, T.-L., Zou, J.-Q., Wang, L., Wang, G., Liu, Y.-J., Ding, X.-J., Zhang, B., Sun, P., et al. (2019) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2019.12.063 · Cited by 24 · see citing works
Choi, D., Cai, E. P., Schroer, S. A., Wang, L., & Woo, M. (2011) · Laboratory Investigation · doi:10.1038/labinvest.2010.207 · Cited by 23 · see citing works
All-encomPASsing regulation of β-cells: PAS domain proteins in β-cell dysfunction and diabetes.
Sabatini, P. V., & Lynn, F. (2015) · Trends in endocrinology and metabolism · doi:10.1016/j.tem.2014.11.002 · Cited by 22 · see citing works
Lecomte, M., Pechberty, S., Machado, C., Barroca, S. D., Ravassard, P., Scharfmann, R., Czernichow, P., & Duvillié, B. (2016) · Cell Medicine · doi:10.3727/215517916x692843 · Cited by 21 · see citing works
L-Glucose: Another Path to Cancer Cells
Ono, K., Takigawa, S., & Yamada, K. (2020) · Cancers · doi:10.3390/cancers12040850 · Cited by 20 · see citing works
Millán‐Uclés, Á., Castro, B. D., García‐Flores, P., Báez, A., Pérez‐Simón, J. A., López‐Barneo, J., & Piruat, J. I. (2014) · PLoS ONE · doi:10.1371/journal.pone.0085528 · Cited by 19 · see citing works
“As a control, protein extracts from a tissue-specific knock-out mouse for pVHL [34] showed induced expression of Hif1a.”
BackgroundPathogenesis of diabetic complications: Exploring hypoxic niche formation and HIF-1α activation
Bi, J., Zhou, W., & Tang, Z. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116202 · Cited by 19 · see citing works
Maintenance of ischemic β cell viability through delivery of lipids and ATP by targeted liposomes
Atchison, N., Swindlehurst, G. R., Papas, K., Tsapatsis, M., & Kokkoli, E. (2014) · Biomaterials Science · doi:10.1039/c3bm60094g · Cited by 19 · see citing works
Hypoxia inducible factor-1α is necessary for invasive phenotype in Vegf-deleted islet cell tumors
Takeda, T., Okuyama, H., Nishizawa, Y., Tomita, S., & Inoue, M. (2012) · Scientific Reports · doi:10.1038/srep00494 · Cited by 19 · see citing works
HIF1α and pancreatic β‐cell development
Heinis, M., Soggia, A., Bechetoille, C., Simon, M., Peyssonnaux, C., Rustin, P., Scharfmann, R., & Duvillié, B. (2012) · The FASEB Journal · doi:10.1096/fj.11-199224 · Cited by 17 · see citing works
“Recently, it was shown that the deletion of the Vhl-floxed allele mediated by pdx1-Cre caused the activation of HIF1 in all pancreatic cell types and resulted in a normal -cell mass at 12 wk of age (20).”
BackgroundInfluentialWang, Y., Liu, S., Ying, L., Zhang, K., Li, H., Liang, N., Xiao, L., & Luo, G. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms251910534 · Cited by 17 · see citing works
“To assess whether HIF-1 α expression These fi ndings indicate that NMN holds potential as a promising therapeutic agent for addressing β -cell dysfunction caused by PA. mediates PA-induced pancreatic β -cell dysfunction, INS-1 cells were exposed to PA alone or in combination with PX-478, an”
BackgroundResultInfluentialRoles of β-Cell Hypoxia in the Progression of Type 2 Diabetes
Yamagata, K., Tsuyama, T., & Sato, Y. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25084186 · Cited by 19 · see citing works
Role of prolyl hydroxylase domain proteins in the regulation of insulin secretion
Huang, M., Paglialunga, S., Wong, J., Hoang, M., Pillai, R., & Joseph, J. (2016) · Physiological Reports · doi:10.14814/phy2.12722 · Cited by 18 · see citing works
“While this finding contradict the current results in b-cells as well as those obtained from VHL KO mice, which display HIF1a protein stabilization, delayed glucose tolerance, and blunted GSIS in isolated islets (Cantley et al. 2009; Puri et al. 2009), again this supports the notion of a tissue-specific function.”
ResultVon Hippel-Lindau Disease (VHL): A need for a murine model with retinal hemangioblastoma
Park, S., & Chan, C.-C. (2012) · Histology and Histopathology · doi:10.14670/hh-27.975 · Cited by 18 · see citing works
“Mice models, with the exception of one (Shen et al., 2009) showed none of the characteristic pancreatic cysts and neuroendocrine tumors that are seen in patients with VHL (Cantley et al., 2009; Puri et al., 2009; Choi et al., 2011).”
New Insights into Endocrine Pancreatic Development: The Role of Environmental Factors
Heinis, M., Simon, M., & Duvillié, B. (2010) · Hormone Research in Paediatrics · doi:10.1159/000314894 · Cited by 18 · see citing works
Role of hypoxia-inducible factor 1 in type 1 diabetes.
Fagundes, R. R., Zaldumbide, A., & Taylor, C. T. (2024) · TIPS - Trends in Pharmacological Sciences · doi:10.1016/j.tips.2024.07.001 · Cited by 17 · see citing works
Endocrine targets of hypoxia-inducible factors
Lee, H.-C., & Tsai, S. (2017) · Journal of Endocrinology · doi:10.1530/joe-16-0653 · Cited by 20 · see citing works
Loss of huntingtin-associated protein 1 impairs insulin secretion from pancreatic β-cells
Cape, A., Chen, X., Wang, C.-E., O’Neill, A., Lin, Y., He, J., Xu, X., Yi, H. L., He, L., Li, S., et al. (2011) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-011-0692-8 · Cited by 16 · see citing works
“Thus, we examined pancreatic islets isolated from Hap1 KO and control mice to measure static insulin release using the established assays [33–35].”
MethodElimination of Von Hippel-Lindau Function Perturbs Pancreas Endocrine Homeostasis in Mice
Puri, S., García-Núñez, A., Hebrok, M., & Cano, D. (2013) · PLoS ONE · doi:10.1371/journal.pone.0072213 · Cited by 15 · see citing works
“Total pancreas inactivation of Vhlh using a Pdx-1-Cre (pancreatic and duodenal homeobox gene-1 promoter) transgenic mouse line causes glucose intolerance, similar to what has been observed in mice with deletion of Vhlh in ß-cells, but no other pancreatic abnormalities are observed [3].”
BackgroundInfluentialSweet and Sour β-Cells: ROS and Hif1α Induce Warburg-Like Lactate Production During Type 2 Diabetes
Cantley, J., & Biden, T. (2013) · Diabetes · doi:10.2337/db13-0272 · Cited by 14 · see citing works
“For example, b-cell glucose uptake is disrupted by Hif1a activation (12,14), suggesting that there may be additional Hif1a-induced defects in GK islets besides the lactate shunt.”
BackgroundSelf-citationHIF-2α Preserves Mitochondrial Activity and Glucose Sensing in Compensating β-Cells in Obesity
Moon, J.-S., Riopel, M., Seo, J. B., Herrero-Aguayo, V., Isaac, R., & Lee, Y. S. (2022) · Diabetes · doi:10.2337/db21-0736 · Cited by 13 · see citing works
Huang, Y.-K., Hu, W.-W., & Huang, X.-G. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.963469 · Cited by 12
“In fact, animal studies have shown that loss of the VHL gene in islet b cells leads to impaired glucose tolerance in mice, but whether this is associated with pancreatic tumors remains unclear (24, 25).”
BackgroundSuzuki, K., Sato, Y., Kai, S., Nishi, K., Adachi, T., Matsuo, Y., & Hirota, K. (2015) · PeerJ · doi:10.7717/peerj.1498 · Cited by 12 · see citing works
“, 2011), while a forced artificial increase in HIF-1α protein and HIF-1 activity levels caused by genetic ablation of the von Hippel Lindau (VHL) protein in mouse pancreatic β-cells attenuated GSIS and increased lactate levels (Cantley et al., 2009; Puri, Cano & Hebrok, 2009; Zehetner et al., 2008).”
BackgroundHyperoxia reverses glucotoxicity-induced inhibition of insulin secretion in rat INS-1 β cells
Matsunaga, T., Li, S.-H., Adachi, T., Joo, E., Gu, N., Yamazaki, H., Yasuda, K., Kondoh, T., & Tsuda, K. (2014) · Bioscience, biotechnology and biochemistry · doi:10.1080/09168451.2014.905175 · Cited by 12 · see citing works
Kurabayashi, A., Kakinuma, Y., Morita, T., Inoue, K., Sato, T., & Furihata, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0069139 · Cited by 12
“also suggested that b cells that lacked VHL had abnormalities in glucose sensing and that the VHL/HIF pathway was critical for regulating mammalian pancreatic b cell function [28].”
BackgroundSoggia, A., Ramond, C., Akiyama, H., Scharfmann, R., & Duvillié, B. (2014) · Diabetologia · doi:10.1007/s00125-014-3365-y · Cited by 11 · see citing works
“shows similarities to HIF1-α, was not stabilised in the pancreases of Ins-Cre;Vhl or Pdx1-Cre;Vhl knockout mice [20].”
BackgroundResultInfluentialVascularization of the Pancreas: An Evolving Role From Embryogenesis to Adulthood
Duvillié, B. (2013) · Diabetes · doi:10.2337/db13-1421 · Cited by 10
Prolyl-4-hydroxylase 3 maintains β cell glucose metabolism during fatty acid excess in mice
Nasteska, D., Cuozzo, F., Viloria, K., Johnson, E. M., Thakker, A., Bakar, R. B., Westbrook, R. L., Barlow, J. P., Hoang, M., Joseph, J. W., et al. (2021) · JCI Insight · doi:10.1172/jci.insight.140288 · Cited by 8 · see citing works
“Glucose and KCl-stimulated Ca fluxes, shown to be 326 sensitive to HIF stabilization (49), were similar in βPHD3CON and βPHD3KO islets exposed 327 to hypoxia (Supplementary figure 2E-H).”
Self-citationDown-regulation of CASK in glucotoxicity-induced insulin dysfunction in pancreatic &bgr; cells
Wang, Y., Hao, N.-N., Lin, H.-Y., Wang, T.-Y., Xie, J., & Yuan, Y.-X. (2018) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmx139 · Cited by 9 · see citing works
“Deletion of the VHL gene in pancreatic β cells leads to impaired glucose homeostasis in mice [28].”
BackgroundIntolerant of glucose and gasping for oxygen
Gribble, F. (2009) · Nature Medicine · doi:10.1038/nm0309-247 · Cited by 9 · see citing works
- 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 › Surgery › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
