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Cited by 1,482Pancreatic function and diabetesNitric Oxide and Endothelin EffectsRedox biology and oxidative stress

Are oxidative stress-activated signaling pathways mediators of insulin resistance and β-cell dysfunction?

Open access
Evans, Joseph L., Goldfine, Ira D., Maddux, Betty A., Grodsky, Gerold M.·2003·Diabetes
DOI 10.2337/diabetes.52.1.1
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Abstract

In both type 1 and type 2 diabetes, diabetic complications in target organs arise from chronic elevations of glucose. The pathogenic effect of high glucose, possibly in concert with fatty acids, is mediated to a significant extent via increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and subsequent oxidative stress. ROS and RNS directly oxidize and damage DNA, proteins, and lipids. In addition to their ability to directly inflict damage on macromolecules, ROS and RNS indirectly induce damage to tissues by activating a number of cellular stress-sensitive pathways. These pathways include nuclear factor-kappaB, p38 mitogen-activated protein kinase, NH(2)-terminal Jun kinases/stress-activated protein kinases, hexosamines, and others. In addition, there is evidence that in type 2 diabetes, the activation of these same pathways by elevations in glucose and free fatty acid (FFA) levels leads to both insulin resistance and impaired insulin secretion. Therefore, we propose here that the hyperglycemia-induced, and possibly FFA-induced, activation of stress pathways plays a key role in the development of not only the late complications in type 1 and type 2 diabetes, but also the insulin resistance and impaired insulin secretion seen in type 2 diabetes.

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  • ROS can function as signaling molecules to activate MAPK family, including ERK, p38, and JNK.

    “ROS can function as signaling molecules to activate the MAPK family, including ERK, p38, and JNK (15, 25).”

    From Mitochondrial Fission Contributes to Mitochondrial Dysfunction and Insulin Resistance in Skeletal Muscle (2012) · cites this paper as [15]

  • Mitochondrial metabolism is also required for the transient, controlled production of ROS, which is required for the mitochondrial signaling pathways that trigger granule exocytosis.

    “Mitochondrial metabolism is also required for the transient, controlled production of ROS, which is required for the mitochondrial signaling pathways that trigger granule exocytosis (239, 240).”

    From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [239]

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Research works printed but not linked: 2

  1. DeFronzo RA: Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes. Diabetes Review 5:177-269, 1997
  2. Robertson RP, Harmon JS, Tanaka Y, Sacchi G, Tran PO, Gleason CE, Poitout V: Glucose toxicity of the ␤-cell: cellular and molecular mecha- nisms. In Diabetes Mellitus: A Fundamental and Clinical Text. Le Roith D, Taylor SI, Olefsky JM, Eds. Philadelphia, Lippincott Williams & Wilkins, 2000, p. 125-132

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Authors
Evans, J. L., Goldfine, I. D., Maddux, B. A., & Grodsky, G. M.
Affiliations
  • Medical Research Institute, San Francisco, California
  • University of California, San Francisco (US)
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2003-01-01
Volume
52
Issue
1
Pages
1-8
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/diabetes.52.1.1
OpenAlex
W2059467226
Cited by
1,482
References
105
Citations by year
2026: 24 · 2025: 42 · 2024: 42 · 2023: 48 · 2022: 52 · 2021: 50 · 2020: 66 · 2019: 74 · 2018: 69 · 2017: 75 · 2016: 77 · 2015: 92 · 2014: 92 · 2013: 88 · 2012: 89
FWCI
10.31
Type
journal article
Language
en
Open access
Locations
  • Diabetes (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Diabetes Association
  • Diabetes Action Research and Education Foundation
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
oxidative stress, reactive oxygen species, reactive nitrogen species, insulin resistance, beta-cell dysfunction, impaired insulin secretion, type 2 diabetes, type 1 diabetes, hyperglycemia, free fatty acids, NF-κB, p38 MAPK, hexosamine biosynthetic pathway, diabetes complications
MeSH terms
Animals, Diabetes Mellitus, Type 2, Humans, Hyperglycemia, Insulin Resistance, Islets of Langerhans, Signal Transduction, Oxidative Stress

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