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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Research Article|
November 22 2013
Novel insights into pancreatic β-cell glucolipotoxicity from real-time functional analysis of mitochondrial energy metabolism in INS-1E insulinoma cells
Jonathan Barlow;
Jonathan Barlow
*School of Biomedical and Healthcare Sciences, Plymouth University, Drake Circus, Plymouth PL4 8AA, U.K.
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Charles Affourtit
Charles Affourtit
1
*School of Biomedical and Healthcare Sciences, Plymouth University, Drake Circus, Plymouth PL4 8AA, U.K.
1To whom correspondence should be addressed (email charles.affourtit@plymouth.ac.uk).
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Publisher: Portland Press Ltd
Received:
July 30 2013
Revision Received:
September 20 2013
Accepted:
October 08 2013
Accepted Manuscript online:
October 08 2013
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem J (2013) 456 (3): 417–426.
Article history
Received:
July 30 2013
Revision Received:
September 20 2013
Accepted:
October 08 2013
Accepted Manuscript online:
October 08 2013
Citation
Jonathan Barlow, Charles Affourtit; Novel insights into pancreatic β-cell glucolipotoxicity from real-time functional analysis of mitochondrial energy metabolism in INS-1E insulinoma cells. Biochem J 15 December 2013; 456 (3): 417–426. doi: https://doi.org/10.1042/BJ20131002
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