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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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“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
The role of hypoxia-inducible factors in metabolic diseases
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“…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
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“metabolism, and insulin secretion (37).”
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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 330
Metabolism, hypoxia and the diabetic heart
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The hypoxia response pathway and β ‐cell function
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“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., Li, L., Liu, D., Jovin, I. S., Russell, R. R., Johnson, R. S., Lorenzo, A. D., & Giordano, F. J. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1209281109 · Cited by 114
“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
“(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
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Systemic VHL gene functions and the VHL disease
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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 87
“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. M., Cheng, K., Scott, C. H., & Gunton, J. E. (2012) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2012.05.003 · Cited by 77
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“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
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“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].”
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“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
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The impact of acute caloric restriction on the metabolic phenotype in male C57BL/6 and DBA/2 mice
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“…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. C., Yesildag, B., Berra, E., Ruas, J. L., Pereira, T., & Berggren, P. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.aba9112 · Cited by 72
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“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. J., & Ashford, M. L. J. (2010) · Biochemical Journal · doi:10.1042/bj20100231 · Cited by 54
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
Impaired hypoxia-inducible factor (HIF) regulation by hyperglycemia
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“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. M., Moreno‐Navarrete, J. M., West, C. C., Stewart, K. J., Fernández‐Real, J. M., Schofield, C. J., Seckl, J. R., & Ratcliffe, P. J. (2014) · Diabetes · doi:10.2337/db14-0233 · Cited by 59
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. N., Jung, M.-H., Weinberg, A., Cowley, M. J., Whitworth, P. T., Kaplan, W. H., Hawthorne, W. J., O’Connell, P. J., Weir, G. C., et al. (2013) · Cell Transplantation · doi:10.3727/096368912x658728 · Cited by 58
Self-citationMitochondria mediated cell death in diabetes
Szabadkai, G., & Duchen, M. R. (2009) · APOPTOSIS · doi:10.1007/s10495-009-0363-5 · Cited by 54
“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].”
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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
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“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. A., Abuelgasim, K. A., Nouraie, M. S., Salomón-Andonie, J., Niu, X., Miasnikova, G., Polyakova, L. A., Sergueeva, A., Okhotin, D. J., Cherqaoui, R., et al. (2012) · Journal of Molecular Medicine · doi:10.1007/s00109-012-0961-5 · Cited by 49
“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
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 40
Jeelani, I., Moon, J.-S., da Cunha, F. F., Nasamran, C. A., Jeon, S., Zhang, X., Bandyopadhyay, G. K., Dobaczewska, K., Mikulski, Z., Hosseini, M., et al. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.adi0284 · Cited by 50
Peiris, H. S., Raghupathi, R., Jessup, C. F., Zanin, M., Mohanasundaram, D., Mackenzie, K. D., Chataway, T., Clarke, J. N., Brealey, J. K., Coates, P. T., et al. (2012) · Endocrinology · doi:10.1210/en.2011-2149 · Cited by 56
“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
“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 dialog
Villasenor, A., & Cleaver, O. B. (2012) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2012.06.003 · Cited by 38
High glucose–induced ubiquitination of G6PD leads to the injury of podocytes
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“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., Chen, H., Tan, Q., Huang, J., Zhou, S., Luo, F., Zhang, D., Yang, J., Li, C., Chen, B., et al. (2022) · Bone Research · doi:10.1038/s41413-021-00165-x · Cited by 35
“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
“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
“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 41
Uncovering the gene regulatory network of type 2 diabetes through multi-omic data integration
Liu, J., Liu, S., Yu, Z., Qiu, X., Jiang, R., & Li, W. (2022) · Journal of Translational Medicine · doi:10.1186/s12967-022-03826-5 · Cited by 34
“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 43
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 32
“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 38
D’Hoker, J., Leu, N. D., Heremans, Y., Baeyens, L., Minami, K., Cai, Y., Lavens, A., Chintinne, M., Stangé, G. M., Magenheim, J., et al. (2013) · Diabetes · doi:10.2337/db12-1827 · Cited by 25
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
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 30
Tsuyama, T., Sato, Y., Yoshizawa, T., Matsuoka, T., & Yamagata, K. (2023) · EMBO Reports · doi:10.15252/embr.202256227 · Cited by 42
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
Self-citationBohuslavová, R., Čerychová, R., Nepomucká, K., & Pavlínková, G. (2017) · BMC Endocrine Disorders · doi:10.1186/s12902-017-0200-8 · Cited by 33
“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
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 28
Liu, N., Cai, X., Liu, T., Zou, J., Wang, L., Wang, G., Liu, Y., Ding, X., Zhang, B., Sun, P., et al. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.12.063 · Cited by 30
Choi, D., Cai, E. P., Schroer, S. A., Wang, L., & Woo, M. (2011) · Laboratory Investigation · doi:10.1038/labinvest.2010.207 · Cited by 23
All-encomPASsing regulation of β-cells: PAS domain proteins in β-cell dysfunction and diabetes
Sabatini, P. V., & Lynn, F. C. (2014) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2014.11.002 · Cited by 19
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
L-Glucose: Another Path to Cancer Cells
Ono, K., Takigawa, S., & Yamada, K. (2020) · Cancers · doi:10.3390/cancers12040850 · Cited by 27
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
“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
Maintenance of ischemic β cell viability through delivery of lipids and ATP by targeted liposomes
Atchison, N., Swindlehurst, G. R., Papas, K. K., Michael Tsapatsis, B., & Kokkoli, E. (2014) · Biomaterials Science · doi:10.1039/c3bm60094g · Cited by 22
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 22
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 21
“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 18
“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 20
Role of prolyl hydroxylase domain proteins in the regulation of insulin secretion
Huang, M., Paglialunga, S., Wong, J. M.-K., Hoang, M., Pillai, R., & Joseph, J. W. (2016) · Physiological Reports · doi:10.14814/phy2.12722 · Cited by 14
“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. (2012) · PubMed · doi:10.14670/hh-27.975 · Cited by 14
“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
Role of hypoxia-inducible factor 1 in type 1 diabetes
Fagundes, R. R., Zaldumbide, A., & Taylor, C. T. (2024) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2024.07.001 · Cited by 20
Endocrine targets of hypoxia-inducible factors
Lee, H.-C., & Tsai, S. (2017) · Journal of Endocrinology · doi:10.1530/joe-16-0653 · Cited by 22
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
“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. A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0072213 · Cited by 12
“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
“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
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 21
“, 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., 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 13
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 12
“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 9
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
“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
“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
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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