The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index.
Superoxide-mediated activation of uncoupling protein 2 causes pancreatic β cell dysfunction
Open accessAbstract
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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“Additional work by Krauss et al. (176) showed that induction of UCP2 by endogenous superoxide impaired insulin secretion from isolated islets in WT but not UCP2 KO mice.”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [176]
Citations
Cites
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Cited by
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Free radicals and antioxidants in normal physiological functions and human disease
Valko, M., Leibfritz, D., Moncol, J., Cronin, M. T. D., Mazur, M., & Telser, J. (2007) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2006.07.001 · Cited by 14,269
Mitochondrial dysfunction and type 2 diabetes
Lowell, B. B., & Shulman, G. I. (2005) · Science · doi:10.1126/science.1104343 · Cited by 2,070
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Metadata
- 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)
- 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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