High Glucose Enhances Neurotoxicity and Inflammatory Cytokine Secretion by Stimulated Human Astrocytes
Abstract
BACKGROUND: Chronic neuroinflammation caused by activation of microglia and astrocytes in the brain contributes to neuronal loss and disease progression in Alzheimer's disease (AD). Recent research has identified type 2 diabetes mellitus (T2DM) as a risk factor for AD. High blood glucose (hyperglycemia) and the phenomenon of insulin resistance are being considered as the major factors contributing to an increased risk of AD. However, the mechanisms involved in this interaction remain unclear. OBJECTIVE: High glucose has been shown to increase release of pro-inflammatory mediators from various immune cells, including microglia. Since astrocytes are the most abundant glial cell type in the brain, we investigated the effects of elevated glucose concentrations (5.5-30.5 mM) on selected functions of cultured human astrocytes in the presence of inflammatory stimuli. METHOD: Experiments were conducted using primary human astrocytes and U-118 MG astrocytoma cells. RESULTS: High glucose (30.5 mM) increased mRNA expression of interleukin (IL)-6 and secretion of both IL-6 and IL-8 by astrocytes. This astrocytic inflammatory response to high glucose did not appear to be mediated by augmented p38 or p44/42 mitogen activated protein kinase (MAPK) signaling pathways. In addition, high glucose increased the susceptibility of undifferentiated human SH-SY5Y neuronal cells and retinoic-acid differentiated SH-SY5Y cells to injury by hydrogen peroxide (H2O2) and fibrillar amyloid beta-42 protein (Aβ42), respectively. CONCLUSION: Our data indicate that hyperglycemia in T2DM may be one of the factors contributing to the observed increased risk of AD by exacerbating astrocyte-mediated neuroinflammation and neuronal injury caused by disease-associated agents.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Astrocytes exposed to high glucose in vitro secreted more IL-6 and Interleukin 8.
“Bahniwal et al. reported that astrocytes exposed to high glucose in vitro secreted more IL-6 and Interleukin 8.112”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [112]
Cites
Still being checked.
Cited by
Sorted by citations
Role of neuroinflammation in neurodegeneration development
Zhang, W., Xiao, D., Mao, Q., & Xia, H. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01486-5 · Cited by 1,668 · see citing works
“reported that astrocytes exposed to high glucose in vitro secreted more IL-6 and Interleukin 8.(112) Moreover, microglial response to lipopolysaccharide (LPS), a known inflammation inducer, is enhanced under high glucose conditions.”
BackgroundGonzález-Reyes, R. E., Nava-Mesa, M. O., Vargas-Sánchez, K., Ariza-Salamanca, D. F., & Mora-Muñoz, L. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00427 · Cited by 525 · see citing works
Neuroinflammation in Alzheimer’s Disease
Onyango, I. G., Jauregui, G. V., Čarná, M., Bennett, J. P., & Stokin, G. B. (2021) · Biomedicines · doi:10.3390/biomedicines9050524 · Cited by 330 · see citing works
Ryu, K., Lee, H., Woo, H., Kang, R.-J., Han, K., Park, H., Lee, S. M., Lee, J., Jeong, Y. J., Nam, H.-W., et al. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1561-x · Cited by 160 · see citing works
Alzheimer’s Disease and Inflammaging
Kosyreva, A., Sentyabreva, A., Tsvetkov, I., & Makarova, O. (2022) · Brain Sciences · doi:10.3390/brainsci12091237 · Cited by 98 · see citing works
Bhattamisra, S. K., Koh, H. M., Lim, S. Y., Choudhury, H., & Pandey, M. (2021) · Biomolecules · doi:10.3390/biom11020323 · Cited by 96 · see citing works
The Potential Role of Cytokines and Growth Factors in the Pathogenesis of Alzheimer’s Disease
Ogunmokun, G., Dewanjee, S., Chakraborty, P., Valupadas, C., Chaudhary, A., Kolli, V., Anand, U., Vallamkondu, J., Goel, P., Paluru, H. P. R., et al. (2021) · Cells · doi:10.3390/cells10102790 · Cited by 85 · see citing works
Unchiti, K., Leurcharusmee, P., Samerchua, A., Pipanmekaporn, T., Chattipakorn, N., & Chattipakorn, S. C. (2021) · European Journal of Neuroscience · doi:10.1111/ejn.15474 · Cited by 85 · see citing works
A New Human Blood–Retinal Barrier Model Based on Endothelial Cells, Pericytes, and Astrocytes
Fresta, C. G., Fidilio, A., Caruso, G., Caraci, F., Giblin, F. J., Leggio, G. M., Salomone, S., Drago, F., & Bucolo, C. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21051636 · Cited by 79 · see citing works
Hypothalamic inflammation in metabolic disorders and aging
Bhusal, A., Rahman, M. H., & Suk, K. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-04019-x · Cited by 79 · see citing works
Neurodegeneration in type 2 diabetes: Alzheimer's as a case study
Madhusudhanan, J., Suresh, G., & Devanathan, V. (2020) · Brain and Behavior · doi:10.1002/brb3.1577 · Cited by 76 · see citing works
Dietary Fiber and Telomere Length in 5674 U.S. Adults: An NHANES Study of Biological Aging
Tucker, L. A. (2018) · Nutrients · doi:10.3390/nu10040400 · Cited by 69 · see citing works
Midlife lipid and glucose levels are associated with Alzheimer's disease
Zhang, X., Tong, T., Chang, A., Ang, T. F. A., Tao, Q., Auerbach, S., Devine, S., Qiu, W. Q., Mez, J., Massaro, J., et al. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.12641 · Cited by 65 · see citing works
Metabolic perspective of astrocyte dysfunction in Alzheimer's disease and type 2 diabetes brains.
Shen, Z., Li, Z., Yu, M., Tan, K., & Chen, S. (2023) · Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · doi:10.1016/j.biopha.2022.114206 · Cited by 43 · see citing works
Ebokaiwe, A. P., Okori, S. O., Nwankwo, J. O., Ejike, C. E. C. C., & Osawe, S. O. (2020) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-020-02000-2 · Cited by 53 · see citing works
Asslih, S., Damri, O., & Agam, G. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22116138 · Cited by 48 · see citing works
Price, J. B., Bronars, C. A., Erhardt, S., Cullen, K., Schwieler, L., Berk, M., Walder, K. R., McGee, S. L., Frye, M. A., & Tye, S. J. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.04.002 · Cited by 47 · see citing works
Khan, M. S., Ikram, M. A., Park, T. J., & Kim, M. O. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/4051207 · Cited by 45 · see citing works
Yonamine, C. Y., Michalani, M. L. E., Moreira, R. J., & Machado, U. F. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242216480 · Cited by 50 · see citing works
Hypothalamic neuropeptides and neurocircuitries in Prader Willi syndrome
Corrêa-da-Silva, F., Fliers, E., Swaab, D., & Yi, C. (2021) · Journal of neuroendocrinology · doi:10.1111/jne.12994 · Cited by 34 · see citing works
11β-HSD as a New Target in Pharmacotherapy of Metabolic Diseases
Kupczyk, D., Bilski, R., Kozakiewicz, M., Studzińska, R., Kędziora–Kornatowska, K., Kosmalski, T., Pedrycz, A., & Głowacka, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23168984 · Cited by 40 · see citing works
Ding, Y., Liu, Y., Fei, F., Yang, L., Mao, G., Zhao, T. K., Zhang, Z., Yan, M., Feng, W., & Wu, X. (2019) · Toxicology · doi:10.1016/j.tox.2019.05.011 · Cited by 31 · see citing works
Gao, X., Sun, H., Wei, Y.-D., Niu, J., Hao, S., Sun, H., Tang, G., Qi, C., & Ge, J. (2024) · Phytomedicine · doi:10.1016/j.phymed.2024.155805 · Cited by 30 · see citing works
Morsy, M. A., Khalaf, H. M., Rifaai, R. A., Bayoumi, A. M. A., Khalifa, E. M. M. A., & Ibrahim, Y. F. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111902 · Cited by 30 · see citing works
Ding, Y., Gao, K., Liu, Y., Mao, G., Chen, K., Qiu, X., Zhao, T., Yang, L., Feng, W., & Wu, X. (2019) · Archives of Toxicology · doi:10.1007/s00204-019-02590-8 · Cited by 30 · see citing works
Zhang, W., Hong, J., Zheng, W., Liu, A., & Yang, Y. (2021) · Aging · doi:10.18632/aging.203136 · Cited by 29 · see citing works
Demi̇r, E., Nedzvetsky, V. S., Ağca, C. A., & Kırıcı, M. (2020) · Neurochemical Research · doi:10.1007/s11064-020-03097-w · Cited by 27 · see citing works
Wu, L., Chen, Y., Wang, C.-Y., Tang, Y.-Y., Huang, H., Kang, X., Li, X., Xie, Y.-R., & Tang, X. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00194 · Cited by 27 · see citing works
Jung, Y.-H., Kim, H., Jeon, S. Y., Kwon, J. M., Lee, W. J., Kim, Y. C., Jang, J. H., Choi, S., Lee, J., & Kang, D. (2018) · Pain Medicine · doi:10.1093/pm/pny111 · Cited by 26 · see citing works
Experimental cell models of insulin resistance: overview and appraisal
Yang, Y., Wang, T., Xie, H.-A., Hu, P. P., & Pan, L. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1469565 · Cited by 24 · see citing works
Ge, H., Sun, M., Wei, X., Zhang, M., Tu, H., Hao, Y., Chen, R., Ye, M., & Gao, Y. (2020) · Purinergic Signalling · doi:10.1007/s11302-020-09752-9 · Cited by 24 · see citing works
Li, X., Yu, P., Yu, Y., Xu, T., Liu, J., Cheng, Y. G., Yang, X., Cui, X., Cui, Y., & Liu, Y. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.107545 · Cited by 24 · see citing works
Daniele, G., Campi, B., Saba, A., Codini, S., Ciccarone, A., Giusti, L., Prato, S. D., ESTERLINE, R. L., & Ferrannini, E. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00216 · Cited by 22 · see citing works
Huang, Y., Hsu, S.-M., Shie, F., Shiao, Y., Chao, L.-J., Chen, H., Yao, H.-H., Chien, M. A., Lin, C., & Tsay, H.-J. (2022) · PLoS ONE · doi:10.1371/journal.pone.0260966 · Cited by 17 · see citing works
Spinal neuron-glial crosstalk and ion channel dysregulation in diabetic neuropathic pain
Wu, J., Hu, H., & Li, X. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1480534 · Cited by 15 · see citing works
Supasitthumrong, T., Tunvirachaisakul, C., Aniwattanapong, D., Tangwongchai, S., Chuchuen, P., Tawankanjanachot, I., Snabboon, T., Hemrungrojn, S., Carvalho, A. F., & Maes, M. (2019) · Journal of Alzheimer’s Disease · doi:10.3233/jad-190114 · Cited by 13 · see citing works
Díaz‐Amarilla, P., Arredondo, F., Dapueto, R., Boix, V., Carvalho, D. B., Santi, M. D., Vasilskis, E., Mesquita-Ribeiro, R., Dajas‐Bailador, F., Abin‐Carriquiry, J. A., et al. (2022) · Neurochemistry International · doi:10.1016/j.neuint.2022.105403 · Cited by 12 · see citing works
Holstein, D. M., Saliba, A., Lozano, D., Kim, J., Sharma, K., & Lechleiter, J. D. (2025) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x251334222 · Cited by 11 · see citing works
Fouda, M. A., El-Sayed, S. S., & Abdel‐Rahman, A. A. (2017) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.117.243865 · Cited by 11 · see citing works
Dementia in diabetes mellitus and atherosclerosis: Two interrelated systemic diseases
Moghaddam, P. M., Ghobadian, R., & Khaleghzadeh‐Ahangar, H. (2022) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2022.01.018 · Cited by 10 · see citing works
Weng, L., Lu, Y., Song, H., Xu, J., & Jiang, X. (2025) · Frontiers in Neurology · doi:10.3389/fneur.2024.1478884 · Cited by 10 · see citing works
da Rosa, P. M., Meira-Martins, L. A., Souza, D. O., Bobermin, L. D., Quincozes‐Santos, A., & Leite, M. C. (2019) · Molecular Biology Reports · doi:10.1007/s11033-019-04930-4 · Cited by 9 · see citing works
Indari, O., Jakhmola, S., Pathak, D. K., Tanwar, M., Kandpal, M., Mishra, A., Kumar, R., & Jha, H. C. (2022) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.2c00081 · Cited by 10 · see citing works
Potential Glioprotective Strategies Against Diabetes-Induced Brain Toxicity
Sovrani, V., Bobermin, L. D., Schmitz, I., Leipnitz, G., & Quincozes‐Santos, A. (2021) · Neurotoxicity Research · doi:10.1007/s12640-021-00393-3 · Cited by 9 · see citing works
Tekmeh, H. H., Kural, B. V., Kör, S., Malkoç, M. A., Yuluğ, E., Kutlu, A., Abidin, İ., & Örem, A. (2023) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2023.05.039 · Cited by 9 · see citing works
A systematic review of in vivo brain insulin resistance biomarkers in humans
Reid, G., Sargent, B., Bauermeister, S., Adler, A., & Koychev, I. G. (2025) · Biomarkers in Neuropsychiatry · doi:10.1016/j.bionps.2025.100125 · Cited by 8 · see citing works
Cohen, S. S., Liu, Q., Wright, M., Garvin, J., Rarick, K. R., & Harder, D. R. (2019) · Heliyon · doi:10.1016/j.heliyon.2019.e01795 · Cited by 8 · see citing works
Gholami, M., Sadegh, M., Koroush-arami, M., Norouzi, S., Arismani, R. J., Asadi, E., Amini, M., & Khodayari, N. (2023) · Inflammopharmacology · doi:10.1007/s10787-023-01347-1 · Cited by 8 · see citing works
Tang, Y., Yin, H., Wang, W., Zhang, X., Chu, N., Li, S., Yan, C., Fu, Q., & Yao, K. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.118360 · Cited by 7 · see citing works
Reniers, P., Leontjevas, R., Stoyanov, S., Knippenberg, I. A. H., van Lankveld, J. J. D. M., & Gerritsen, D. L. (2019) · International Psychogeriatrics · doi:10.1017/s1041610219001339 · Cited by 6 · see citing works
Long-Term Porcine Retina Explants as an Alternative to In Vivo Experimentation
Weller, M., Müller, B., & Stieger, K. (2024) · Translational Vision Science & Technology · doi:10.1167/tvst.13.3.9 · Cited by 6 · see citing works
Song, Z., Yu, W., Jin, Y., Zhou, M.-F., He, C., Li, Z., He, J., Chen, Q., Li, P., Yi, Y., et al. (2025) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2025.120352 · Cited by 6 · see citing works
Jin, Z., Zhai, X., Yingfei, B., Hu, J., Yu, H., Sang, J.-J., Wu, M., & Hao, F. (2026) · Frontiers in Nutrition · doi:10.3389/fnut.2025.1696066 · Cited by 4 · see citing works
Guso, E., Lupoli, A., Olivieri, E., Bottoni, A., Gironi, M., Missarelli, D. M., Toosy, A., Rossi, E., & Furlan, R. (2026) · Neuroscience · doi:10.1016/j.neuroscience.2026.02.047 · Cited by 4 · see citing works
Low-Concentrations of Fatty Acids Induce an Early Increase in IL-8 Levels in Normal Human Astrocytes
Dobri, A.-M., Codrici, E., Popescu, I. D., Albulescu, L., Fertig, T. E., Enciu, A., Tănase, C., & Hinescu, M. E. (2022) · Metabolites · doi:10.3390/metabo12040329 · Cited by 4 · see citing works
Dafnis, I., Mountaki, C., Fanarioti, Ε., Mastellos, D. C., Karvelas, M., Karathanos, V. Τ., Tzinia, A. K., Dermon, C. R., & Chroni, A. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-03047-3 · Cited by 4 · see citing works
Bárány, Z. B., Tóth, I., Jócsák, G., Frenyó, L. V., Bartha, T., Sterczer, Á., & Kiss, D. S. (2021) · Clinical and Experimental Neuroimmunology · doi:10.1111/cen3.12650 · Cited by 3 · see citing works
Hakami, A., Rizzo, S. A., Bartley, O. J. M., Hills, R., Precious, S. V., Ostler, T., Fjodorova, M., Alghamdi, M. A., Rosser, A., Lane, E. L., et al. (2025) · Neurotherapeutics · doi:10.1016/j.neurot.2024.e00518 · Cited by 2 · see citing works
Kancsev, A., Engh, M. A., Horváth, A., Hegyi, P., Kelemen, O., & Kéri, S. (2025) · Schizophrenia · doi:10.1038/s41537-025-00694-y · Cited by 2 · see citing works
Chanoumidou, K., Zota, I., Papadopoulou, M. A., Konstantinou, C., Tsimpolis, A., Tsagliotis, E., Tziortziou, M., Ntarntani, K., Grünewald, A., Lavigne, M. D., et al. (2026) · Stem Cell Research & Therapy · doi:10.1186/s13287-026-04965-y · Cited by 2 · see citing works
The pivotal role of immunometabolism in diabetic neuropathy and its potential therapeutic strategies
Lin, R., Zhang, X., Yang, X. J., Tang, R., Bao, T., & Zhao, L. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1791057 · Cited by 2 · see citing works
Forti, P., & Maioli, F. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12051794 · Cited by 2 · see citing works
Supasitthumrong, T., Tunvirachaisakul, C., Aniwattanapong, D., Tangwongchai, S., Chuchuen, P., Tawankanjanachot, I., Snabboon, T., Hemrungrojn, S., Carvalho, A. F., & Maes, M. H. J. (2019) · Preprints.org · doi:10.20944/preprints201901.0296.v1 · Cited by 2 · see citing works
Singh, J., Dhokne, M. D., Kumar, D., Datusalia, A. K., & Jangra, A. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-13195-0.00011-9 · Cited by 1 · see citing works
Diabetes Differentially Alters Glial Cells in Different Brain Regions
Kumari, R., Willing, L. B., & McLaughlin, P. J. (2025) · Diabetology · doi:10.3390/diabetology6030016 · Cited by 1 · see citing works
Khan, M. S., Ahmad, A., Nasiripour, S., & Bopassa, J. C. (2026) · Journal of dementia and Alzheimer's disease · doi:10.3390/jdad3010005 · Cited by 1 · see citing works
High glucose levels sensitize neuron-like cells to damage induced by oxidative and neurotoxic agents
Lima, J. E. B. D. F., Moreira, N. C. D. S., Piassi, L. D. O., Ono, R. M. D. S., & Sakamoto‐Hojo, E. T. (2026) · Scientific Reports · doi:10.1038/s41598-026-52267-3 · Cited by 1 · see citing works
Immunology of Alzheimer’s disease
Sosa-García, L. I., Hernández-Jiménez, J., Moral, D. I. D., Duyckaerts, C. J., & Calderón‐Garcidueñas, A. L. (2019) · Revista de Fomento Social · doi:10.24875/rmn.19000010
Heo, S. H. (2021) · Stroke revisited · doi:10.1007/978-981-16-5123-6_4
Shared pathways in Alzheimer’s disease and type 2 diabetes mellitus
Karmakar, A., Dutta, S., & Mukhopadhyay, D. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-33355-2.00036-0
Sahu, S. R., Roy, P., & Upadhyay, R. K. (2026) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2025.111402
Hippocampal Lipocalin-2 in T2DM Associated Neurodegeneration: A Therapeutic Perspective
Panigrahy, B., Mukherjee, A., & Singh, S. (2026) · Neurochemical Research · doi:10.1007/s11064-026-04765-z
- Authors
- Bahniwal, M., Little, J. P., & Klegeris, A.
- Affiliations
- University of British Columbia, Okanagan Campus (CA)
- Corresponding author
- Klegeris, Andis
- Venue
- Current Alzheimer Research
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2017-06-19
- Volume
- 14
- Issue
- 7
- Pages
- 731-741
- ISSN
- 1567-2050 (ISSN-L)
- OpenAlex
- W2585979483
- Cited by
- 72
- References
- 0
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 4 · 2023: 6 · 2022: 9 · 2021: 14 · 2020: 7 · 2019: 10 · 2018: 3 · 2017: 2
- FWCI
- 3.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Alzheimer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Keywords
- hyperglycemia, type 2 diabetes, astrocytes, neuroinflammation, Alzheimer's disease, interleukin-6, interleukin-8, MAPK signaling, hydrogen peroxide, amyloid-beta 42, neuronal injury, insulin resistance
- MeSH terms
- Analysis of Variance, Astrocytes, Cell Differentiation, Cell Line, Transformed, Cell Survival, Dose-Response Relationship, Drug, Gene Expression Regulation, Glucose, Humans, Neuroblastoma, Neurons, Peptide Fragments, RNA, Messenger, Sweetening Agents, Time Factors, Signal Transduction, Cytokines, Amyloid beta-Peptides, p38 Mitogen-Activated Protein Kinases
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
