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    Basal fatty acid oxidation increases after recurrent low glucose in human primary astrocytes

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    Publication date
    2019-01
    Author
    Weightman Potter, P.G.
    Vlachaki Walker, J.M.
    Robb, J.L.
    Chilton, J.K.
    Williamson, Ritchie
    Randall, A.D.
    Ellacott, K.L.J.
    Beall, C.
    Keyword
    Adenosine triphosphate
    AMP-activated protein kinase
    Astrocyte
    Diabetes
    Fatty acid oxidation
    Glia
    Hypoglycaemia
    Lactate
    Low glucose
    Mitochondrial metabolism
    Rights
    © The Author(s) 2018. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
    Peer-Reviewed
    Yes
    
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    Abstract
    Aims/hypothesis Hypoglycaemia is a major barrier to good glucose control in type 1 diabetes. Frequent hypoglycaemic episodes impair awareness of subsequent hypoglycaemic bouts. Neural changes underpinning awareness of hypoglycaemia are poorly defined and molecular mechanisms by which glial cells contribute to hypoglycaemia sensing and glucose counterregulation require further investigation. The aim of the current study was to examine whether, and by what mechanism, human primary astrocyte (HPA) function was altered by acute and recurrent low glucose (RLG). Methods To test whether glia, specifically astrocytes, could detect changes in glucose, we utilised HPA and U373 astrocytoma cells and exposed them to RLG in vitro. This allowed measurement, with high specificity and sensitivity, of RLG-associated changes in cellular metabolism. We examined changes in protein phosphorylation/expression using western blotting. Metabolic function was assessed using a Seahorse extracellular flux analyser. Immunofluorescent imaging was used to examine cell morphology and enzymatic assays were used to measure lactate release, glycogen content, intracellular ATP and nucleotide ratios. Results AMP-activated protein kinase (AMPK) was activated over a pathophysiologically relevant glucose concentration range. RLG produced an increased dependency on fatty acid oxidation for basal mitochondrial metabolism and exhibited hallmarks of mitochondrial stress, including increased proton leak and reduced coupling efficiency. Relative to glucose availability, lactate release increased during low glucose but this was not modified by RLG. Basal glucose uptake was not modified by RLG and glycogen levels were similar in control and RLG-treated cells. Mitochondrial adaptations to RLG were partially recovered by maintaining euglycaemic levels of glucose following RLG exposure. Conclusions/interpretation Taken together, these data indicate that HPA mitochondria are altered following RLG, with a metabolic switch towards increased fatty acid oxidation, suggesting glial adaptations to RLG involve altered mitochondrial metabolism that could contribute to defective glucose counterregulation to hypoglycaemia in diabetes.
    URI
    http://hdl.handle.net/10454/16628
    Version
    published version paper
    Citation
    Weightman Potter PG, Vlachaki Walker JM, Robb JL et al (2019) Basal fatty acid oxidation increases after recurrent low glucose in human primary astrocytes. Diabetologia. 62(1): 187-198.
    Link to publisher’s version
    https://doi.org/10.1007/s00125-018-4744-6
    Type
    Article
    Collections
    Life Sciences Publications

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