The Role of Oxidative Stress and Hypoxia in Pancreatic Beta-Cell Dysfunction in Diabetes Mellitus

Gerber, Philipp A.; Rutter, Guy A.

doi:10.1089/ars.2016.6755

Cited by 654Pancreatic function and diabetesEndoplasmic Reticulum Stress and DiseaseDiabetes Treatment and Management

The Role of Oxidative Stress and Hypoxia in Pancreatic Beta-Cell Dysfunction in Diabetes Mellitus

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Gerber, Philipp A., Rutter, Guy A.·2017·Antioxidants & Redox Signaling

DOI 10.1089/ars.2016.6755PMC PMC5372767

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Abstract

Significance: Metabolic syndrome is a frequent precursor of type 2 diabetes mellitus (T2D), a disease that currently affects ∼8% of the adult population worldwide. Pancreatic beta-cell dysfunction and loss are central to the disease process, although understanding of the underlying molecular mechanisms is still fragmentary. Recent Advances: Oversupply of nutrients, including glucose and fatty acids, and the subsequent overstimulation of beta cells, are believed to be an important contributor to insulin secretory failure in T2D. Hypoxia has also recently been implicated in beta-cell damage. Accumulating evidence points to a role for oxidative stress in both processes. Although the production of reactive oxygen species (ROS) results from enhanced mitochondrial respiration during stimulation with glucose and other fuels, the expression of antioxidant defense genes is unusually low (or disallowed) in beta cells. Critical Issues: Not all subjects with metabolic syndrome and hyperglycemia go on to develop full-blown diabetes, implying an important role in disease risk for gene–environment interactions. Possession of common risk alleles at the SLC30A8 locus, encoding the beta-cell granule zinc transporter ZnT8, may affect cytosolic Zn 2+ concentrations and thus susceptibility to hypoxia and oxidative stress. Future Directions: Loss of normal beta-cell function, rather than total mass, is increasingly considered to be the major driver for impaired insulin secretion in diabetes. Better understanding of the role of oxidative changes, its modulation by genes involved in disease risk, and effects on beta-cell identity may facilitate the development of new therapeutic strategies to this disease. Antioxid. Redox Signal . 26, 501–518.

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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, 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 [240]
The section “Roles of hypoxia-inducible factors in pancreatic beta cells” (page unavailable) links sustained HIF activation to disturbed beta-cell function and impaired glucose tolerance in VHL-deficient mice. But it reports that fasting insulin secretion was unchanged or increased, probably because ATP production rose—not that HIF signaling reduced ATP production. The passages also do not establish glucotoxicity or oxidative stress as drivers of the HIF-mediated effect claimed here. (LLM, conf=0.86)
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“This modiﬁcation leads to oxygen concentration-independent stabilization of HIFs (25, 153, 210).”
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Intracellular zinc in insulin secretion and action: a determinant of diabetes risk?
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Molecular mechanisms of ROS production and oxidative stress in diabetes
Newsholme, P., Cruzat, V. F., Keane, K. N., Carlessi, R., & de Bittencourt, P. I. H. (2016) · Biochemical Journal · doi:10.1042/bcj20160503c · Cited by 878 · see citing works
Oxidative stress mitigation by antioxidants - An overview on their chemistry and influences on health status
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Hyperglycemia and Oxidative Stress: An Integral, Updated and Critical Overview of Their Metabolic Interconnections
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Molecular Mechanisms Linking Oxidative Stress and Diabetes Mellitus
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Mitochondrial dynamics in type 2 diabetes: Pathophysiological implications
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Oxidative stress and diabetes: antioxidative strategies
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Oxidative Stress: Pathogenetic Role in Diabetes Mellitus and Its Complications and Therapeutic Approaches to Correction
Darenskaya, M. A., Колесникова, Л. И., & Kolesnikov, S. I. (2021) · Bulletin of Experimental Biology and Medicine · doi:10.1007/s10517-021-05191-7 · Cited by 488 · see citing works
Breakdown of an Ironclad Defense System: The Critical Role of NRF2 in Mediating Ferroptosis
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The Role of the Pentose Phosphate Pathway in Diabetes and Cancer
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Melatonin and its metabolites vs oxidative stress: From individual actions to collective protection
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β Cell dysfunction during progression of metabolic syndrome to type 2 diabetes
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Oxidative stress: Roles in skeletal muscle atrophy
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Sirtuins and Type 2 Diabetes: Role in Inflammation, Oxidative Stress, and Mitochondrial Function
Kitada, M., Ogura, Y., Monno, I., & Koya, D. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00187 · Cited by 289 · see citing works
Oxidative stress in biological systems and its relation with pathophysiological functions: the effect of physical activity on cellular redox homeostasis
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Computational strategies for predicting free radical scavengers' protection against oxidative stress: Where are we and what might follow?
Galano, A., & Alvarez-Idaboy, J. R. (2018) · International Journal of Quantum Chemistry · doi:10.1002/qua.25665 · Cited by 282 · see citing works
Vitamin D deficiency and diabetes
Berridge, M. J. (2017) · Biochemical Journal · doi:10.1042/bcj20170042 · Cited by 265 · see citing works
Oxidative Stress in Pancreatic Beta Cell Regeneration
Wang, J., & Wang, H. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/1930261 · Cited by 236 · see citing works
Oxidative stress pathways in pancreatic β-cells and insulin-sensitive cells and tissues: importance to cell metabolism, function, and dysfunction
Newsholme, P., Keane, K. N., Carlessi, R., & Cruzat, V. F. (2019) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00141.2019 · Cited by 225 · see citing works
Oxidative stress in diabetes mellitus and its complications: From pathophysiology to therapeutic strategies
Chen, X., Xie, N., Feng, L., Huang, Y., Wu, Y., Zhu, H., Tang, J., & Zhang, Y. (2024) · Chinese Medical Journal · doi:10.1097/cm9.0000000000003230 · Cited by 186 · see citing works
A new research hot spot: The role of NLRP3 inflammasome activation, a key step in pyroptosis, in diabetes and diabetic complications
Yu, Z.-W., Zhang, J., Li, X., Wang, Y., Fu, Y., & Gao, X. (2019) · Life Sciences · doi:10.1016/j.lfs.2019.117138 · Cited by 181 · see citing works
Quercetin for managing type 2 diabetes and its complications, an insight into multitarget therapy
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M2 macrophage-derived exosomes promote diabetic fracture healing by acting as an immunomodulator
Wang, Y., Lin, Q., Zhang, H., Wang, S., Cui, J., Hu, Y., Liu, J., Li, M., Zhang, K., Zhou, F., et al. (2023) · Bioactive Materials · doi:10.1016/j.bioactmat.2023.05.018 · Cited by 170 · see citing works
Oxidative stress-mediated beta cell death and dysfunction as a target for diabetes management
Dinić, S., Јovanović, J. A., Uskoković, A. S., Mihailović, M., Grdović, N., Tolić, A., Rajić, J., Đorđević, M., & Vidaković, M. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1006376 · Cited by 186 · see citing works
Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies
Mirzaei, S., Hushmandi, K., Zabolian, A., Saleki, H., Torabi, S. M., Ranjbar, A., SeyedSaleh, S., Sharifzadeh, S. O., Khan, H. Z., Ashrafizadeh, M., et al. (2021) · Molecules · doi:10.3390/molecules26082382 · Cited by 150 · see citing works
Interplay between oxidative stress, SIRT1, reproductive and metabolic functions
Alam, F., Syed, H., Amjad, S., Baig, M., Khan, T. A., & Rehman, R. (2021) · Current Research in Physiology · doi:10.1016/j.crphys.2021.03.002 · Cited by 151 · see citing works
Zinc in Pancreatic Islet Biology, Insulin Sensitivity, and Diabetes
Maret, W. (2017) · Preventive Nutrition and Food Science · doi:10.3746/pnf.2017.22.1.1 · Cited by 147 · see citing works
Oxidative Stress and Cardiovascular Complications in Type 2 Diabetes: From Pathophysiology to Lifestyle Modifications
Caturano, A., Rocco, M. P., Tagliaferri, G., Piacevole, A., Nilo, D., Lorenzo, G. D., Iadicicco, I., Donnarumma, M., Galiero, R., Acierno, C., et al. (2025) · Antioxidants · doi:10.3390/antiox14010072 · Cited by 162 · see citing works
Oxidative stress: The nexus of obesity and cognitive dysfunction in diabetes
Li, H., Ren, J. L., Li, Y., Wu, Q., & Wei, J. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1134025 · Cited by 148 · see citing works
Metabolic Syndrome and Oxidative Stress: A Complex Relationship
Carrier, A. (2016) · Antioxidants and Redox Signaling · doi:10.1089/ars.2016.6929 · Cited by 118 · see citing works
An evaluation on potential anti-oxidant and anti-inflammatory effects of Crocin
Bastani, S., Vahedian, V., Rashidi, M., Mir, A., Mirzaei, S., Alipourfard, I., Pouremamali, F., Nejabati, H. R., Kadkhoda, J., Maroufi, N. F., et al. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113297 · Cited by 115 · see citing works
Short Chain Fatty Acids, pancreatic dysfunction and type 2 diabetes
Mandaliya, D. K., & Seshadri, S. (2019) · Pancreatology · doi:10.1016/j.pan.2019.01.021 · Cited by 112 · see citing works
Glucose as a Major Antioxidant: When, What for and Why It Fails?
Cherkas, A., Holota, S. M., Мдзинарашвили, Т., Gabbianelli, R., & Žarković, N. (2020) · Antioxidants · doi:10.3390/antiox9020140 · Cited by 111 · see citing works
Beta-Cell Mass in Obesity and Type 2 Diabetes, and Its Relation to Pancreas Fat: A Mini-Review
Inaishi, J., & Saisho, Y. (2020) · Nutrients · doi:10.3390/nu12123846 · Cited by 113 · see citing works
Reversing pancreatic β-cell dedifferentiation in the treatment of type 2 diabetes
Son, J., & Accili, D. (2023) · Experimental and Molecular Medicine · doi:10.1038/s12276-023-01043-8 · Cited by 96 · see citing works
Nrf2: The Master and Captain of Beta Cell Fate
Baumel-Alterzon, S., Katz, L. S., Brill, G., Garcı́a-Ocaña, A., & Scott, D. K. (2020) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2020.11.002 · Cited by 105 · see citing works
Oxidative stress markers in the follicular fluid of patients with polycystic ovary syndrome correlate with a decrease in embryo quality
Liu, Y., Yu, Z., Zhao, S., Cheng, L., Man, Y., Gao, X., & Zhao, H. (2020) · Journal of Assisted Reproduction and Genetics · doi:10.1007/s10815-020-02014-y · Cited by 103 · see citing works
Diabetic Muscular Atrophy: Molecular Mechanisms and Promising Therapies
Shen, Y., Li, M., Wang, K., Qi, G., Liu, H., Wang, W., Ji, Y., Chang, M., Deng, C., Xu, F., et al. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.917113 · Cited by 103 · see citing works
Lipotoxicity and β Cell Maintenance in Obesity and Type 2 Diabetes
Ye, R., Onodera, T., & Scherer, P. E. (2019) · Journal of the Endocrine Society · doi:10.1210/js.2018-00372 · Cited by 94 · see citing works
Safeguarding Osteointegration in Diabetic Patients: A Potent “Chain Armor” Coating for Scavenging ROS and Macrophage Reprogramming in a Microenvironment‐Responsive Manner
He, Q., Yuan, S., Tang, H., Wang, S., Mu, Z., Li, D., Wang, S., Jing, X., Hu, S., Ji, P., et al. (2021) · Advanced Functional Materials · doi:10.1002/adfm.202101611 · Cited by 97 · see citing works
The Distinct Effects of Palmitic and Oleic Acid on Pancreatic Beta Cell Function: The Elucidation of Associated Mechanisms and Effector Molecules
Nemecz, M., Constantin, A. L., Dumitrescu, M., Alexandru, N., Filippi, A., Tanko, G., & Georgescu, A. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.01554 · Cited by 94 · see citing works
Shortened Leukocyte Telomere Length Is Associated With Glycemic Progression in Type 2 Diabetes: A Prospective and Mendelian Randomization Analysis
Cheng, F., Luk, A. O. Y., Shi, M., Huang, C., Jiang, G., Yang, A., Wu, H., Lim, C. K. P., Tam, C. H. T., Fan, B., et al. (2022) · Diabetes Care · doi:10.2337/dc21-1609 · Cited by 92 · see citing works
Genetic risk converges on regulatory networks mediating early type 2 diabetes
Walker, J. T., Saunders, D. C., Rai, V., Chen, H., Orchard, P., Dai, C., Pettway, Y. D., Hopkirk, A. L., Reihsmann, C., Tao, Y., et al. (2023) · Nature · doi:10.1038/s41586-023-06693-2 · Cited by 89 · see citing works
Signaling pathways and intervention for therapy of type 2 diabetes mellitus
Cao, R. Y., Tian, H., Zhang, Y., Liu, G., Xu, H., Rao, G., Tian, Y., & Fu, X. (2023) · MedComm · doi:10.1002/mco2.283 · Cited by 87 · see citing works
FOXO1 Overexpression Attenuates Tubulointerstitial Fibrosis and Apoptosis in Diabetic Kidneys by Ameliorating Oxidative Injury via TXNIP-TRX
Ji, L., Wang, Q., Huang, F., An, T., Guo, F., Zhao, Y., Liu, Y., He, Y., Song, Y., & Qin, G. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/3286928 · Cited by 87 · see citing works
The Interlinked Rising Epidemic of Insufficient Sleep and Diabetes Mellitus
Chattu, V. K., Chattu, S. K., Burman, D., Spence, D. W., & Pandi-Perumal, S. R. (2019) · Healthcare · doi:10.3390/healthcare7010037 · Cited by 87 · see citing works
Molecular aspects of pancreatic β‐cell dysfunction: Oxidative stress, microRNA, and long noncoding RNA
Borujeni, M. J. S., Esfandiary, E., Baradaran, A., Valiani, A., Ghanadian, M., Codoñer‐Franch, P., Basirat, R., Alonso‐Iglesias, E., Mirzaei, H., & Yazdani, A. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.27755 · Cited by 86 · see citing works
LC–MS/MS analysis and network pharmacology of Trigonella foenum-graecum – A plant from Ayurveda against hyperlipidemia and hyperglycemia with combination synergy
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Authors: Gerber, P. A., & Rutter, G. A.
Affiliations: University Hospital Zurich (CH)
Imperial College London (GB)
Corresponding author: Rutter, Guy A.
ORCID: Gerber, Philipp A.
Rutter, Guy A.
Venue: Antioxidants & Redox Signaling
Publisher: SAGE Publications
Published: 2017-04
Volume: 26
Issue: 10
Pages: 501-518
ISSN: 1523-0864 (ISSN-L)
1557-7716
DOI: 10.1089/ars.2016.6755
PMC: PMC5372767
OpenAlex: W2405977822
Cited by: 654
References: 218
Citations by year: 2026: 50 · 2025: 67 · 2024: 69 · 2023: 95 · 2022: 87 · 2021: 82 · 2020: 85 · 2019: 64 · 2018: 36 · 2017: 16 · 2016: 3
FWCI: 7.86
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)
Locations: Antioxidants and Redox Signaling (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
Spiral (Imperial College London) (submittedVersion)
Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
Zurich Open Repository and Archive (University of Zurich)
Funders: Wellcome Trust (FP7/2007–2013, WT098424AIA)
European Federation of Pharmaceutical Industries and Associations (FP7/20072013)
Diabetes UK (11/0004210)
European Commission (2007–2013, FP7 2007-2013, FP7/2007)
Universitätsspital Zürich
Innovative Medicines Initiative (FP7/2007‐2013, 155005)
Directorate for Biological Sciences
Medical Research Council (MR/K001981/1, MR/J0003042/1)
Biotechnology and Biological Sciences Research Council (BB/J015873/1)
Topics: Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords: oxidative stress, hypoxia, beta-cell dysfunction, type 2 diabetes, insulin secretion, reactive oxygen species, mitochondrial respiration, antioxidant defense genes, metabolic syndrome, SLC30A8, zinc transporter 8, zinc, gene-environment interaction, beta-cell identity
MeSH terms: Animals, Hypoxia, Antioxidants, Diabetes Mellitus, Diabetes Mellitus, Type 2, Glucose, Humans, Insulin, Islets of Langerhans, Mitochondria, Zinc, Islets of Langerhans Transplantation, Reactive Oxygen Species, Oxidative Stress, Lipid Metabolism, Insulin-Secreting Cells

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The Role of Oxidative Stress and Hypoxia in Pancreatic Beta-Cell Dysfunction in Diabetes Mellitus

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