Cited by 1,961Adipokines, Inflammation, and Metabolic DiseasesAdvanced Glycation End Products researchDiabetes Management and Research

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Inflammatory Cytokine Concentrations Are Acutely Increased by Hyperglycemia in Humans: Role of Oxidative Stress

Esposito, Katherine, Nappo, Francesco, Marfella, Raffaele, Giugliano, Giovanni, Giugliano, Francesco, Ciotola, Myriam, Quagliaro, Lisa, Ceriello, Antonio, Giugliano, Dario·2002·Circulation

DOI 10.1161/01.cir.0000034509.14906.ae

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Abstract

Background— Circulating levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) are elevated in diabetic patients. We assessed the role of glucose in the regulation of circulating levels of IL-6, TNF-α, and interleukin-18 (IL-18) in subjects with normal or impaired glucose tolerance (IGT), as well as the effect of the antioxidant glutathione. Methods and Results— Plasma glucose levels were acutely raised in 20 control and 15 IGT subjects and maintained at 15 mmol/L for 5 hours while endogenous insulin secretion was blocked with octreotide. In control subjects, plasma IL-6, TNF-α, and IL-18 levels rose ( P <0.01) within 2 hours of the clamp and returned to basal values at 3 hours. In another study, the same subjects received 3 consecutive pulses of intravenous glucose (0.33 g/kg) separated by a 2-hour interval. Plasma cytokine levels obtained at 3, 4, and 5 hours were higher ( P <0.05) than the corresponding values obtained during the clamp. The IGT subjects had fasting plasma IL-6 and TNF-α levels higher ( P <0.05) than those of control subjects. The increase in plasma cytokine levels during the clamping lasted longer (4 hours versus 2 hours, P <0.01) in the IGT subjects than in the control subjects, and the cytokine peaks of IGT subjects after the first glucose pulse were higher ( P <0.05) than those of control subjects. On another occasion, 10 control and 8 IGT subjects received the same glucose pulses as above during an infusion of glutathione; plasma cytokine levels did not show any significant change from baseline after the 3 glucose pulses. Conclusions— Hyperglycemia acutely increases circulating cytokine concentrations by an oxidative mechanism, and this effect is more pronounced in subjects with IGT. This suggests a causal role for hyperglycemia in the immune activation of diabetes.

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Background
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Background
Cardiovascular effects of acute hyperglycaemia: pathophysiological underpinnings
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Small extracellular vesicle-loaded bevacizumab reduces the frequency of intravitreal injection required for diabetic retinopathy
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“…which could be contributing to inflammatory response as hyperglycemia is directly linked with increased levels of pro-inflammatory cytokines [58] Alternatively the dose of VEGF and duration of treatment also could be contributing to the effectiveness in suppressing the inflammation as both…”
Background
Oxidative stress and antioxidant status in elderly diabetes mellitus and glucose intolerance patients
Atlı, T., Keven, K., Avcı, A., Kutlay, S., Türkçapar, N., Varlı, M., Aras, S., Ertuğ, E., & Canbolat, O. (2004) · Archives of Gerontology and Geriatrics · doi:10.1016/j.archger.2004.04.065 · Cited by 73
“It was reported that hyperglycemia (particularly post-prandial in IGT subjects) could be a trigger for acute increases of circulating cytokine concentrations by an oxidative mechanism, and this effect is more pronounced in subjects with IGT (Esposito et al., 2002).”
Background
Pre-Clinical Study for the Antidiabetic Potential of Selenium Nanoparticles
Ahmed, H. H., Abdelmaksoud, M. D. E., Moneim, A. E. A., & Aglan, H. A. (2016) · Biological Trace Element Research · doi:10.1007/s12011-016-0876-z · Cited by 76
Association of biomarkers of inflammation and oxidative stress with the risk of chronic kidney disease in Type 2 diabetes mellitus in North Indian population
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Background
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Hyperglycemia and Outcome in the Pediatric Intensive Care Unit
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Sustained IL-1α, IL-4, and IL-6 elevations following correction of hyperglycemia in children with type 1 diabetes mellitus
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“While some work in this field was performed in adults with T2DM (11, 28), our study is the first in children with T1DM, a surprisingly understudied patient population exceptionally vulnerable to repetitive and prolonged hyperglycemia.”
ResultInfluential
Multiple Antioxidants Improve Cardiac Complications and Inhibit Cardiac Cell Death in Streptozotocin-Induced Diabetic Rats
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“Hyperglycemia activates several cytokines by oxidative mechanisms, which might contribute to the development of diabetic cardiomyopathy [30].”
Background
Hyperglycemia in Aneurysmal Subarachnoid Hemorrhage: A Potentially Modifiable Risk Factor for Poor Outcome
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“The cause of DCI in aSAH patients remains unclear, but various mechanisms have been proposed that may be influenced by hyperglycemia.”
BackgroundInfluential
A review of the anti‐inflammatory properties of antidiabetic agents providing protective effects against vascular complications in diabetes
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“…cell adhesion molecule‐1 (ICAM‐1), E‐selectin, nuclear factor kappa B (NF‐κb), hypoxia‐induced factor‐α, interleukin‐6 (IL‐6), MCP‐1, and TNF‐α (Aljada et al., 2006; Dandona, Chaudhuri, Ghanim, & Mohanty, 2007; Dhindsa et al., 2004; Esposito et al., 2002; Sun et al., 2014).”
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Lifestyle and Environmental Factors Affecting Male Fertility, Individual Predisposition, Prevention, and Intervention
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Intravenous glucose intake independently related to intensive care unit and hospital mortality: an argument for glucose toxicity in critically ill patients
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Preventive Effects of a Cocoa‐Enriched Diet on Gingival Oxidative Stress in Experimental Periodontitis
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Potential Interplay between Hyperosmolarity and Inflammation on Retinal Pigmented Epithelium in Pathogenesis of Diabetic Retinopathy
Willermain, F., Scifo, L., Weber, C., Caspers, L. E., Perret, J., & Delporte, C. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19041056 · Cited by 72
“In this context of inflammation, hyperglycemia affects Tumor necrosis alpha (TNFα) and interleukin 6 (IL6) plasma levels [68], as well as local VEGF levels [69], while retinal hypoxia induce the release of cytokines, chemokines, and growth factors from macrophages and microglia [70].”
Background
Type 2 diabetes mellitus as inflammatory disease
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Background
Metformin and ascorbic acid combination therapy ameliorates type 2 diabetes mellitus and comorbid depression in rats
Shivavedi, N., Kumar, M., Tej, G. N. V. C., & Nayak, P. K. (2017) · Brain Research · doi:10.1016/j.brainres.2017.08.019 · Cited by 72
Connexin 43 Hemichannel Activity Promoted by Pro-Inflammatory Cytokines and High Glucose Alters Endothelial Cell Function
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Background

Authors: Esposito, K., Nappo, F., Marfella, R., Giugliano, G., Giugliano, F., Ciotola, M., Quagliaro, L., Ceriello, A., & Giugliano, D.
Affiliations: University of Udine (IT)
ORCID: Esposito, Katherine
Marfella, Raffaele
Ceriello, Antonio
Giugliano, Dario
Venue: Circulation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2002-10-15
Volume: 106
Issue: 16
Pages: 2067-2072
ISSN: 0009-7322 (ISSN-L)
1524-4539
DOI: 10.1161/01.cir.0000034509.14906.ae
OpenAlex: W2123560318
Cited by: 1,961
References: 36
Citations by year: 2026: 57 · 2025: 69 · 2024: 88 · 2023: 95 · 2022: 106 · 2021: 91 · 2020: 102 · 2019: 83 · 2018: 86 · 2017: 70 · 2016: 87 · 2015: 112 · 2014: 99 · 2013: 102 · 2012: 101
FWCI: 38.18
Type: journal article
Language: en
Open access: closed
Locations: Circulation (publishedVersion)
PubMed (publishedVersion)
Institutional Research Information System (University of Udine) (submittedVersion)
Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
Keywords: hyperglycemia, inflammatory cytokines, interleukin-6, TNF-α, IL-18, impaired glucose tolerance, glutathione, oxidative stress, glucose clamp
MeSH terms: Adult, Antioxidants, Blood Glucose, Diabetes Mellitus, Type 2, Female, Glucose Tolerance Test, Glutathione, Humans, Inflammation, Kinetics, Male, Tumor Necrosis Factor-alpha, Interleukin-6, Cytokines, Glucose Intolerance, Oxidative Stress, Interleukin-18

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Inflammatory Cytokine Concentrations Are Acutely Increased by Hyperglycemia in Humans: Role of Oxidative Stress

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