dc.contributor.author | Weightman Potter, P | |
dc.contributor.author | Vlachaki Walker, J | |
dc.contributor.author | Robb, J | |
dc.contributor.author | Chilton, J | |
dc.contributor.author | Williamson, R | |
dc.contributor.author | Randall, A | |
dc.contributor.author | Ellacott, K | |
dc.contributor.author | Beall, C | |
dc.date.accessioned | 2018-09-20T12:33:49Z | |
dc.date.issued | 2018-10-06 | |
dc.description.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. | en_GB |
dc.description.sponsorship | This study was funded by grants from: Diabetes UK (RD Lawrence
Fellowship to CB; 13/0004647); the Medical Research Council (MR/N012763/1) to
KLJE, ADR and CB; and a Mary Kinross Charitable Trust PhD studentship to CB,
ADR and RW to support PGWP. Additional support for this work came from awards
from the British Society for Neuroendocrinology (to CB and KLJE), the Society for
Endocrinology (CB), Tenovus Scotland (CB) and the University of Exeter Medical
School (CB and KLJE). AR was also supported by a Royal Society Industry
Fellowship. | en_GB |
dc.identifier.citation | Published online 6 October 2018 | en_GB |
dc.identifier.doi | 10.1007/s00125-018-4744-6 | |
dc.identifier.uri | http://hdl.handle.net/10871/34042 | |
dc.language.iso | en | en_GB |
dc.publisher | Springer Verlag | en_GB |
dc.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. | |
dc.subject | Adenosine triphosphate | en_GB |
dc.subject | AMP-activated protein kinase | en_GB |
dc.subject | Astrocyte | en_GB |
dc.subject | Diabetes | en_GB |
dc.subject | Fatty acid oxidation | en_GB |
dc.subject | Glia | en_GB |
dc.subject | Hypoglycaemia | en_GB |
dc.subject | Lactate | en_GB |
dc.subject | Low glucose | en_GB |
dc.subject | Mitochondrial metabolism | en_GB |
dc.title | Basal fatty acid oxidation increases after recurrent low glucose in human primary astrocytes | en_GB |
dc.type | Article | en_GB |
dc.identifier.issn | 0012-186X | |
dc.description | This is the final version. Available from Springer Verlag via the DOI in this record. | en_GB |
dc.identifier.journal | Diabetologia | en_GB |