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Cited by 242Nitric Oxide and Endothelin EffectsAdvanced Glycation End Products researchAntioxidant Activity and Oxidative Stress

The DOI matches its Crossref record; 14 of the 14 references it cites were found in a registry or an index.

Acute hyperglycemia induces an oxidative stress in healthy subjects

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Marfella, Raffaele, Quagliaro, Lisa, Nappo, Francesco, Ceriello, Antonio, Giugliano, Dario·2001·Journal of Clinical Investigation
DOI 10.1172/jci13727PMC PMC209408
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Abstract

Recent prospective studies indicate that long-term glycemic control of diabetes is an important predictor not only of microvascular disease but also of macrovascular complications, including coronary heart disease (1). Possible links between glucose and cardiovascular events in the diabetic patient include modifications of important vascular functions of the endothelium with a switch from a quiescent, relaxant, antithrombotic, antioxidant, and antiadhesive state to an activated state displaying a more atherogenetic risk profile (2). Generation of reactive oxygen species could be a common downstream mechanism by means of which multiple byproducts of glucose are exerting their adverse effects on blood vessels (3). Indeed, in April 2001, Pennathur et al. (4) reported in the JCI that hyperglycemia favors oxidative reactions in the microenvironment of the artery wall in vivo. We studied the effect of acute elevations of plasma glucose levels on plasma nitrotyrosine, a marker of oxidative stress, in 20 healthy subjects (11 men, 9 women). Their age was 34 ± 4 years (mean ± SD), and the body mass index was 24 ± 1 kg/m2. None used any medication. After giving informed written consent to participate in the study, each subject underwent a hyperglycemic glucose clamp test in which plasma glucose concentrations were acutely raised at about 15 mmol/l for 120 minutes (Figure ​(Figure1).1). Mean blood pressure and nitrotyrosine (5) rose significantly during the clamp; there was a positive correlation (r = 0.49) between nitrotyrosine and mean blood pressure increases during hyperglycemia. In control studies (n = 6), in which plasma glucose was maintained at normal concentrations (5 mmol/l for 120 minutes), we could detect no variation in nitrotyrosine plasma levels from baseline (baseline: 0.15 ± 0.05 μmol/l; 120-minute values: 0.13 ± 0.05 μmol/l, P = not significant). Figure 1 Twenty healthy subjects were submitted to a hyperglycemic glucose clamp study in which plasma glucose levels were acutely raised to 15 mmol/l (0.33 g/kg as intravenous bolus injection followed by a variable 30% glucose infusion). Mean blood pressure ... We show here that acute hyperglycemia in normal subjects causes an oxidative stress as evidenced by the raised circulating nitrotyrosine levels during the hyperglycemic clamp. However, we cannot exclude the possibility that some nitrotyrosine can be generated via a peroxynitrite-independent mechanism, or that a reduced nitrotyrosine clearance during hyperglycemia could also contribute to its raised plasma concentrations. Since nitrotyrosine is considered a good marker of peroxynitrite formation (6), and since peroxynitrite may account for a considerable portion of the toxic effects previously attributed to nitric oxide or the superoxide anion (7), it is possible that some of the toxic effects of hyperglycemia on the vascular tree may be modulated by peroxynitrite. Acute hyperglycemia in normal subjects may in fact induce vasoconstriction, activate thrombosis, increase the circulating levels of soluble adhesion molecules, and prolong the QT interval (8, 9). The recent demonstration (10) that apoptosis of myocytes, endothelial cells, and fibroblasts in heart biopsies taken from diabetic patients is selectively associated with intracellular levels of nitrotyrosine supports a role for high-energy oxidants (such as peroxynitrite) as mediators of the vascular damage brought about by hyperglycemia.

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  1. Cuzzocrea, 2001, Pharmacol Rev, 53, 135

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Metadata

Authors
Marfella, R., Quagliaro, L., Nappo, F., Ceriello, A., & Giugliano, D.
Corresponding author
Giugliano, Dario
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2001-08-15
Volume
108
Issue
4
Pages
635-636
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci13727
PMC
PMC209408
OpenAlex
W2052924362
Cited by
242
References
14
Citations by year
2026: 3 · 2025: 4 · 2024: 4 · 2023: 5 · 2022: 1 · 2021: 5 · 2020: 7 · 2019: 9 · 2018: 4 · 2017: 6 · 2016: 6 · 2015: 7 · 2014: 10 · 2013: 8 · 2012: 12
FWCI
6.19
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Journal of Clinical Investigation (publishedVersion, cc-by)
  • Journal of Clinical Investigation (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (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 › Physiology (medical) › Nitric Oxide and Endothelin Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
  • Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
Keywords
acute hyperglycemia, oxidative stress, nitrotyrosine, glucose clamp, reactive oxygen species, endothelial dysfunction, blood pressure, healthy volunteers, cardiovascular risk, diabetes complications, vascular function, nitrosative stress, nitric oxide, nitric oxide synthase, nitric oxide radical
MeSH terms
Adult, Diabetic Angiopathies, Female, Hemodynamics, Humans, Hydrogen-Ion Concentration, Hyperglycemia, Male, Nitrates, Tyrosine, Vasoconstriction, Glucose Clamp Technique, Biomarkers, Confounding Factors, Epidemiologic, Oxidative Stress

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