Cited by 401Pancreatic function and diabetesMitochondrial Function and PathologyMetabolism, Diabetes, and Cancer

Superoxide-mediated activation of uncoupling protein 2 causes pancreatic β cell dysfunction

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Krauss, Stefan, Zhang, Chen-Yu, Scorrano, Luca, Dalgaard, Louise T., St-Pierre, Julie, Grey, Shane T., Lowell, Bradford B.·2003·Journal of Clinical Investigation

Abstract

Failure to secrete adequate amounts of insulin in response to increasing concentrations of glucose is an important feature of type 2 diabetes. The mechanism for loss of glucose responsiveness is unknown. Uncoupling protein 2 (UCP2), by virtue of its mitochondrial proton leak activity and consequent negative effect on ATP production, impairs glucose-stimulated insulin secretion. Of interest, it has recently been shown that superoxide, when added to isolated mitochondria, activates UCP2-mediated proton leak. Since obesity and chronic hyperglycemia increase mitochondrial superoxide production, as well as UCP2 expression in pancreatic β cells, a superoxide-UCP2 pathway could contribute importantly to obesity- and hyperglycemia-induced β cell dysfunction. This study demonstrates that endogenously produced mitochondrial superoxide activates UCP2-mediated proton leak, thus lowering ATP levels and impairing glucose-stimulated insulin secretion. Furthermore, hyperglycemia- and obesity-induced loss of glucose responsiveness is prevented by reduction of mitochondrial superoxide production or gene knockout of UCP2. Importantly, reduction of superoxide has no beneficial effect in the absence of UCP2, and superoxide levels are increased further in the absence of UCP2, demonstrating that the adverse effects of superoxide on β cell glucose sensing are caused by activation of UCP2. Therefore, superoxide-mediated activation of UCP2 could play an important role in the pathogenesis of β cell dysfunction and type 2 diabetes.

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Crossref · 10.1172/jci200319774

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Authors
Krauss, S., Zhang, C.-Y., Scorrano, L., Dalgaard, L. T., St-Pierre, J., Grey, S. T., & Lowell, B. B.
Affiliations
  • Beth Israel Deaconess Medical Center (US)
  • Roskilde University (DK)
  • Harvard University (US)
Corresponding author
Lowell, Bradford B.
Venue
Journal of Clinical Investigation
Published
2003-12-15
Volume
112
Issue
12
Pages
1831-1842
ISSN
0021-9738 (ISSN-L)
OpenAlex
W2121338998
Cited by
401
References
52
Citations by year
2026: 2 · 2025: 7 · 2024: 10 · 2023: 4 · 2022: 9 · 2021: 12 · 2020: 7 · 2019: 7 · 2018: 10 · 2017: 14 · 2016: 8 · 2015: 23 · 2014: 16 · 2013: 7 · 2012: 24
FWCI
29.08
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion)
Funders
  • American Diabetes Association
  • Sundhed og Sygdom, Det Frie Forskningsråd
  • National Institutes of Health
  • Medical Research Council
  • National Institute of Diabetes and Digestive and Kidney Diseases (R37DK053477)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
UCP2, superoxide, pancreatic beta cells, beta-cell dysfunction, glucose-stimulated insulin secretion, mitochondrial proton leak, mitochondrial superoxide production, ATP depletion, type 2 diabetes, obesity, hyperglycemia
MeSH terms
Uncoupling Protein 2, Insulin Secretion, Adenosine Triphosphate, Animals, Glucose, Hyperglycemia, Insulin, Ion Channels, Islets of Langerhans, Male, Membrane Potentials, Mitochondria, Obesity, Oxygen Consumption, Protons, Rhodamines, RNA, Messenger, Superoxides, Superoxide Dismutase, Thymus Gland, Time Factors, Mice, Knockout, Mitochondrial Proteins, Membrane Transport Proteins, Mice

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