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Cited by 734Nitric Oxide and Endothelin EffectsAdvanced Glycation End Products researchAntioxidant Activity and Oxidative Stress

The DOI matches its Crossref record; 102 of the 102 references it cites were found in a registry or an index.

New Insights on Oxidative Stress and Diabetic Complications May Lead to a “Causal” Antioxidant Therapy

Ceriello, Antonio·2003·Diabetes Care
DOI 10.2337/diacare.26.5.1589
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Abstract

Evidence implicates hyperglycemia-derived oxygen free radicals as mediators of diabetic complications. However, intervention studies with classic antioxidants, such as vitamin E, failed to demonstrate any beneficial effect. Recent studies demonstrate that a single hyperglycemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain seems to be the first and key event in the activation of all other pathways involved in the pathogenesis of diabetic complications. These include increased polyol pathway flux, increased advanced glycosylation end product formation, activation of protein kinase C, and increased hexosamine pathway flux. Superoxide overproduction is accompanied by increased nitric oxide generation, due to an endothelial NOS and inducible NOS uncoupled state, a phenomenon favoring the formation of the strong oxidant peroxynitrite, which in turn damages DNA. DNA damage is an obligatory stimulus for the activation of the nuclear enzyme poly(ADP-ribose) polymerase. Poly(ADP-ribose) polymerase activation in turn depletes the intracellular concentration of its substrate NAD+, slowing the rate of glycolysis, electron transport, and ATP formation, and produces an ADP-ribosylation of the GAPDH. These processes result in acute endothelial dysfunction in diabetic blood vessels that, convincingly, also contributes to the development of diabetic complications. These new findings may explain why classic antioxidants, such as vitamin E, which work by scavenging already-formed toxic oxidation products, have failed to show beneficial effects on diabetic complications and may suggest new and attractive “causal” antioxidant therapy. New low–molecular mass compounds that act as SOD or catalase mimetics or l-propionyl-carnitine and lipoic acid, which work as intracellular superoxide scavengers, improving mitochondrial function and reducing DNA damage, may be good candidates for such a strategy, and preliminary studies support this hypothesis. This “causal” therapy would also be associated with other promising tools such as LY 333531, PJ34, and FP15, which block the protein kinase β isoform, poly(ADP-ribose) polymerase, and peroxynitrite, respectively. While waiting for these focused tools, we may have other options: thiazolinediones, statins, ACE inhibitors, and angiotensin 1 inhibitors can reduce intracellular oxidative stress generation, and it has been suggested that many of their beneficial effects, even in diabetic patients, are due to this property.

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Metadata

Authors
Ceriello, A.
Affiliations
University of Udine (IT)
Corresponding author
Ceriello, Antonio
ORCID
Ceriello, Antonio
Venue
Diabetes Care
Publisher
American Diabetes Association
Published
2003-05-01
Volume
26
Issue
5
Pages
1589-1596
ISSN
  • 0149-5992 (ISSN-L)
  • 1935-5548
DOI
10.2337/diacare.26.5.1589
OpenAlex
W2058550328
Cited by
734
References
102
Citations by year
2026: 9 · 2025: 8 · 2024: 16 · 2023: 15 · 2022: 16 · 2021: 24 · 2020: 13 · 2019: 27 · 2018: 34 · 2017: 41 · 2016: 33 · 2015: 34 · 2014: 46 · 2013: 49 · 2012: 50
FWCI
4.48
Type
journal article
Language
en
Open access
closed
Locations
  • Diabetes Care (publishedVersion)
  • PubMed (publishedVersion)
  • Institutional Research Information System (University of Udine) (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
oxidative stress, diabetes complications, superoxide, mitochondrial electron transport chain, hyperglycemia, polyol pathway, advanced glycation end products, protein kinase C, hexosamine biosynthetic pathway, nitric oxide, peroxynitrite, DNA damage, poly(ADP-ribose) polymerase, NAD+ depletion, endothelial dysfunction, antioxidant therapy, superoxide dismutase mimetic, catalase mimetics, alpha-lipoic acid, PJ34, thiazolidinediones, statins, ACE inhibitors, angiotensin receptor blockers
MeSH terms
Antioxidants, Diabetes Mellitus, DNA Damage, Endothelium, Vascular, Humans, Hyperglycemia, Models, Biological, Oxidative Stress, Peroxynitrous Acid, Diabetes Complications

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