Inflammatory Cytokine Concentrations Are Acutely Increased by Hyperglycemia in Humans: Role of Oxidative Stress
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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Postprandial hypertriglyceridemia has been reported to impair endothelial function in normal and diabetic subjects.
“Similarly, a negative influence of postprandial hypertriglyceridemia on endothelial function has been reported in both normal and diabetic subjects.”
Fluctuations in blood glucose levels may contribute more to outcomes than constant high blood glucose concentrations.
“Other studies have demonstrated that fluctuations in blood glucose levels may contribute more to outcomes than constant high blood glucose concentrations.31–35”
From Increased Time in Range and Fewer Missed Bolus Injections After Introduction of a Smart Connected Insulin Pen (2020) · cites this paper as [32]
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- Authors
- Esposito, K., Nappo, F., Marfella, R., Giugliano, G., Giugliano, F., Ciotola, M., Quagliaro, L., Ceriello, A., & Giugliano, D.
- Affiliations
- University of Udine (IT)
- Venue
- Circulation
- Published
- 2002-10-15
- Volume
- 106
- Issue
- 16
- Pages
- 2067-2072
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- 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 › Epidemiology › 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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