On the role of uncoupling protein-2 in pancreatic beta cells
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Pancreatic beta cells secrete insulin when blood glucose levels are high. Dysfunction of this glucose-stimulated insulin secretion (GSIS) is partly responsible for the manifestation of type 2 diabetes, a metabolic disorder that is rapidly becoming a global pandemic. Mitochondria play a central role in GSIS by coupling glucose oxidation to production of ATP, a signal that triggers a series of events that ultimately leads to insulin release. Beta cells express a mitochondrial uncoupling protein, UCP2, which is rather surprising as activity of such a protein is anticipated to lower the efficiency of oxidative phosphorylation, and hence to impair GSIS. The mounting evidence demonstrating that insulin secretion is indeed blunted by UCP2 agrees with this prediction, and has provoked the idea that UCP2 activity contributes to beta cell pathogenesis and development of type 2 diabetes. Although this notion may be correct, the evolved function of UCP2 remains unclear. With this paper we aim to provide a brief account of the present state of affairs in this field, suggest a physiological role for UCP2, and highlight some of our own recent results.
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UCP2 is a protein present in the beta-cell mitochondria inner membrane, postulated to dampen GSIS by dissipating mitochondrial proton motive force as heat, reducing efficiency of ATP production.
“UCP2 is a protein present in the beta-cell mitochondria inner membrane, which was postulated to dampen GSIS by dissipating mitochondrial proton motive force as heat (due to its analogy with UCP1), thereby reducing the efficiency of ATP production.”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [179]
Approximately 20% of proton leak in beta-cells is thought to occur due to presence of UCP2.
“Approximately 20% of the proton leak in beta-cells is thought to occur due to the presence of UCP2 .178,179”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [179]
Global UCP2 knockout mice exhibit either improved glucose tolerance and GSIS, or unaltered glucose tolerance and impaired GSIS depending on genetic background.
“To further complicate the role of UCP2 in GSIS, in vivo studies have found that global UCP2 knockout mice exhibit either improved glucose tolerance and GSIS, or unaltered glucose tolerance and impaired GSIS depending on their genetic background.179,187”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [179]
Mitochondria, with a major role for UCP2, modulate mitochondrial respiration and membrane potential, ATP production, and therefore insulin release.
“However, these considerations now direct attention to mitochondria with a major role for UCP2 in modulating mitochondrial respiration and membrane potential, ATP production, and therefore insulin release (8).”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [8]
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References 71 · Cited by 78
- Authors
- Affourtit, C., & Brand, M. D.
- Affiliations
- MRC Mitochondrial Biology Unit (GB)
- Corresponding author
- Affourtit, Charles
- Venue
- Biochimica et Biophysica Acta (BBA) - Bioenergetics
- Publisher
- Elsevier BV
- Published
- 2008-07
- Volume
- 1777
- Issue
- 7-8
- Pages
- 973-979
- ISSN
- 0005-2728 (ISSN-L)
- OpenAlex
- W2080219092
- Cited by
- 78
- References
- 71
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 4 · 2023: 1 · 2022: 1 · 2021: 4 · 2020: 2 · 2019: 3 · 2018: 2 · 2017: 4 · 2016: 2 · 2015: 5 · 2014: 5 · 2012: 8
- FWCI
- 1.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Bioenergetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Research Council
- 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, pancreatic beta cells, glucose-stimulated insulin secretion, type 2 diabetes, mitochondrial uncoupling, oxidative phosphorylation, beta-cell dysfunction, insulin secretion
- MeSH terms
- Uncoupling Protein 2, Insulin Secretion, Blood Glucose, Diabetes Mellitus, Type 2, Humans, Insulin, Ion Channels, Mitochondria, Models, Biological, Oxidative Phosphorylation, Oxygen Consumption, Mitochondrial Proteins, Insulin-Secreting Cells
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