Novel insights into pancreatic β-cell glucolipotoxicity from real-time functional analysis of mitochondrial energy metabolism in INS-1E insulinoma cells
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High circulating glucose and non-esterified (free) fatty acid levels can cause pancreatic β-cell failure. The molecular mechanisms of this β-cell glucolipotoxicity are yet to be established conclusively. In the present paper we report on the involvement of mitochondrial dysfunction in fatty-acid-induced β-cell failure. We have used state-of-the-art extracellular flux technology to functionally probe mitochondrial energy metabolism in intact INS-1E insulinoma cells in real-time. We show that 24-h palmitate exposure at high glucose attenuates the glucose-sensitivity of mitochondrial respiration and lowers coupling efficiency of glucose-stimulated oxidative phosphorylation. These mitochondrial defects coincide with an increased level of ROS (reactive oxygen species), impaired GSIS (glucose-stimulated insulin secretion) and decreased cell viability. Palmitate lowers absolute glucose-stimulated respiration coupled to ATP synthesis, but does not affect mitochondrial proton leak. Palmitate is not toxic when administered at low glucose unless fatty acid β-oxidation is inhibited. Palmitoleate, on the other hand, does not affect mitochondrial respiration, ROS levels, GSIS or cell viability. Although palmitoleate protects against the palmitate-induced ROS increase and cell viability loss, it does not protect against respiratory and insulin secretory defects. We conclude that mitochondrial dysfunction contributes to fatty-acid-induced GSIS impairment, and that glucolipotoxic cell viability and GSIS phenotypes are mechanistically distinct.
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Mitochondrial activity during glucolipotoxicity may play an important role in beta-cell survival in vitro and in vivo.
“Hence, mitochondrial activity during glucolipotoxicity may play an important role in beta-cell survival in vitro and in vivo.”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [172]
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- Authors
- Barlow, J., & Affourtit, C.
- Affiliations
- University of Plymouth (GB)
- Corresponding author
- Barlow, Jonathan
- Affourtit, Charles
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2013-11-22
- Volume
- 456
- Issue
- 3
- Pages
- 417-426
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- OpenAlex
- W2032646244
- Cited by
- 53
- References
- 48
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 1 · 2022: 4 · 2021: 6 · 2020: 6 · 2019: 6 · 2018: 7 · 2017: 8 · 2016: 4 · 2015: 5 · 2014: 3
- FWCI
- 3.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed (publishedVersion)
- PEARL (University of Plymouth) (submittedVersion)
- Funders
- University of Exeter
- 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
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- glucolipotoxicity, pancreatic beta-cell failure, mitochondrial dysfunction, mitochondrial bioenergetics, palmitate, palmitoleic acid, fatty acid beta-oxidation, reactive oxygen species, glucose-stimulated insulin secretion, mitochondrial respiration, cell viability, extracellular flux analysis
- MeSH terms
- Insulin Secretion, Adenosine Triphosphate, Animals, Enzyme Inhibitors, Glucose, Insulin, Insulinoma, Mitochondria, Oxidation-Reduction, Oxygen Consumption, Proton-Motive Force, Palmitic Acid, Cell Line, Tumor, Insulin-Secreting Cells, Rats
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