Cited by 542Redox biology and oxidative stressNitric Oxide and Endothelin EffectsAntioxidant Activity and Oxidative Stress

Positive and Negative Regulation of Insulin Signaling by Reactive Oxygen and Nitrogen Species

Bashan, Nava, Kovsan, Julia, Kachko, Ilana, Ovadia, Hilla, Rudich, Assaf·2009·Physiological Reviews

Abstract

Regulated production of reactive oxygen species (ROS)/reactive nitrogen species (RNS) adequately balanced by antioxidant systems is a prerequisite for the participation of these active substances in physiological processes, including insulin action. Yet, increasing evidence implicates ROS and RNS as negative regulators of insulin signaling, rendering them putative mediators in the development of insulin resistance, a common endocrine abnormality that accompanies obesity and is a risk factor of type 2 diabetes. This review deals with this dual, seemingly contradictory, function of ROS and RNS in regulating insulin action: the major processes for ROS and RNS generation and detoxification are presented, and a critical review of the evidence that they participate in the positive and negative regulation of insulin action is provided. The cellular and molecular mechanisms by which ROS and RNS are thought to participate in normal insulin action and in the induction of insulin resistance are then described. Finally, we explore the potential usefulness and the challenges in modulating the oxidant-antioxidant balance as a potentially promising, but currently disappointing, means of improving insulin action in insulin resistance-associated conditions, leading causes of human morbidity and mortality of our era.

Integrity signals

Registry

Crossref · 10.1152/physrev.00014.2008

Cites

488 of 488 references verified0 citation errors · 0 not checkable

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  • Increased ROS in adipocytes exposed to excess free fatty acids does not depend on enhanced mitochondrial flux, but on high levels of TNFα and ER stress as well as upregulation of NOX enzymes.

    “Recently, it has been demonstrated that increased ROS in adipocytes exposed to an excess of FFAs does not depend on enhanced mitochondrial flux, but on high levels of TNFα and ER stress as well as the upregulation of aforementioned NOX enzymes ([8](#B8), [60](#B60)).”

    From Mitochondrial fatty acid oxidation in obesity (2013) · cites this paper as [8]

  • ROS have the capacity to interfere with insulin signaling, since they activate several downstream pathways involving MAPK, JNK/IKKβ, and JAK/STAT, which are key contributors to the development of insulin resistance in obesity and type 2 diabetes.

    “ROS have the capacity to interfere with insulin signaling, since they activate several downstream pathways involving MAPK, JNK/IKKβ, and JAK/STAT, which are key contributors to the development of insulin resistance in obesity and type 2 diabetes ([8](#B8), [75](#B75)).”

    From Mitochondrial fatty acid oxidation in obesity (2013) · cites this paper as [8]

  • In obesity, excess free fatty acids increase NOX-mediated ROS generation.

    “In obesity, the excess of FFAs increases NOX-mediated ROS generation.”

    From Mitochondrial fatty acid oxidation in obesity (2013) · cites this paper as [8]

  • ROS are produced normally during mitochondrial respiration and are essential signal transducers that regulate several cell processes in skeletal muscle, including the insulin pathway.

    “However, these molecules are produced normally during mitochondrial respiration and are essential signal transducers that regulate several cell processes in SkM ([8](#B8)), including the insulin pathway ([64](#B64), [65](#B65)).”

    From Mitochondrial fatty acid oxidation in obesity (2013) · cites this paper as [8]

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Authors
Bashan, N., Kovsan, J., Kachko, I., Ovadia, H., & Rudich, A.
Affiliations
Ben-Gurion University of the Negev (IL)
Venue
Physiological Reviews
Published
2009-01
Volume
89
Issue
1
Pages
27-71
ISSN
  • 0031-9333 (ISSN-L)
  • 1522-1210
OpenAlex
W2110657098
Cited by
542
References
489
Citations by year
2026: 4 · 2025: 20 · 2024: 20 · 2023: 16 · 2022: 28 · 2021: 26 · 2020: 29 · 2019: 42 · 2018: 27 · 2017: 31 · 2016: 39 · 2015: 48 · 2014: 49 · 2013: 43 · 2012: 42
FWCI
3.03
Type
journal article
Language
en
Open access
closed
Locations
  • Physiological Reviews (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
Keywords
insulin signaling, reactive oxygen species, reactive nitrogen species, insulin resistance, type 2 diabetes, obesity, antioxidant defense, prooxidant-antioxidant balance, insulin action, oxidative stress
MeSH terms
Animals, Antioxidants, Humans, Insulin, Insulin Resistance, Signal Transduction, Reactive Oxygen Species, Oxidative Stress, Reactive Nitrogen Species

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