It has been well established that excessive levels of glucose and palmitate lower glucose-stimulated insulin secretion (GSIS) by pancreatic β-cells. This β-cell ‘glucolipotoxicity’ is possibly mediated by mitochondrial dysfunction, but involvement of bioenergetic failure in the pathological mechanism is the subject of ongoing debate. We show in the present study that increased palmitate levels impair GSIS before altering mitochondrial function. We demonstrate that GSIS defects arise from increased insulin release under basal conditions in addition to decreased insulin secretion under glucose-stimulatory conditions. Real-time respiratory analysis of intact mouse pancreatic islets reveals that mitochondrial ATP synthesis is not involved in the mechanism by which basal insulin is elevated. Equally, mitochondrial lipid oxidation and production of reactive oxygen species (ROS) do not contribute to increased basal insulin secretion. Palmitate does not affect KCl-induced insulin release at a basal or stimulatory glucose level, but elevated basal insulin release is attenuated by palmitoleate and associates with increased intracellular calcium. These findings deepen our understanding of β-cell glucolipotoxicity and reveal that palmitate-induced GSIS impairment is disconnected from mitochondrial dysfunction, a notion that is important when targeting β-cells for the treatment of diabetes and when assessing islet function in human transplants.
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February 2016
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Wild type Neuroligin3 (red) localizes to the cell surface in PC12 Tet-on cells, in contrast to proteins within the endoplasmic reticulum (calnexin, green). See pp. 423–434 for further details. Image kindly provided by Ulbrich et al. - PDF Icon PDF LinkFront Matter
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Research Article|
February 09 2016
Palmitate-induced impairment of glucose-stimulated insulin secretion precedes mitochondrial dysfunction in mouse pancreatic islets
Jonathan Barlow;
Jonathan Barlow
*School of Biomedical and Healthcare Sciences, Plymouth University, Drake Circus, Plymouth PL4 8AA, U.K.
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Verena Hirschberg Jensen;
Verena Hirschberg Jensen
*School of Biomedical and Healthcare Sciences, Plymouth University, Drake Circus, Plymouth PL4 8AA, U.K.
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Martin Jastroch;
Martin Jastroch
†Helmholtz Diabetes Center and Institute for Diabetes and Obesity, Garching, Parkring 13, Garching D-85748, Germany
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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:
October 14 2015
Revision Received:
November 20 2015
Accepted:
November 30 2015
Accepted Manuscript online:
November 30 2015
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2016 Authors; published by Portland Press Limited
2016
Biochem J (2016) 473 (4): 487–496.
Article history
Received:
October 14 2015
Revision Received:
November 20 2015
Accepted:
November 30 2015
Accepted Manuscript online:
November 30 2015
Citation
Jonathan Barlow, Verena Hirschberg Jensen, Martin Jastroch, Charles Affourtit; Palmitate-induced impairment of glucose-stimulated insulin secretion precedes mitochondrial dysfunction in mouse pancreatic islets. Biochem J 15 February 2016; 473 (4): 487–496. doi: https://doi.org/10.1042/BJ20151080
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