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

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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

DOI 10.1172/jci200319774PMC PMC297000

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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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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.
ORCID: Scorrano, Luca
Dalgaard, Louise T.
Grey, Shane T.
Lowell, Bradford B.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2003-12-15
Volume: 112
Issue: 12
Pages: 1831-1842
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci200319774
PMC: PMC297000
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: bronze
doi.org
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 › Endocrinology, Diabetes and Metabolism › 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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Superoxide-mediated activation of uncoupling protein 2 causes pancreatic β cell dysfunction

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