Glycogen metabolism protects against metabolic insult to preserve carotid body function during glucose deprivation

Andrew P. Holmes, Philip J. Turner, Paul Carter, Wendy Leadbeater, Clare J. Ray, David Hauton, Keith J. Buckler, Prem Kumar*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

The view that the carotid body (CB) type I cells are direct physiological sensors of hypoglycaemia is challenged by the finding that the basal sensory neuronal outflow from the whole organ is unchanged in response to low glucose. The reason for this difference in viewpoint and how the whole CB maintains its metabolic integrity when exposed to low glucose is unknown. Here we show that, in the intact superfused rat CB, basal sensory neuronal activity was sustained during glucose deprivation for 29.1 ± 1.2 min, before irreversible failure following a brief period of excitation. Graded increases in the basal discharge induced by reducing the superfusate  led to proportional decreases in the time to the pre-failure excitation during glucose deprivation which was dependent on a complete run-down in glycolysis and a fall in cellular energy status. A similar ability to withstand prolonged glucose deprivation was observed in isolated type I cells. Electron micrographs and immunofluorescence staining of rat CB sections revealed the presence of glycogen granules and the glycogen conversion enzymes glycogen synthase I and glycogen phosphorylase BB, dispersed throughout the type I cell cytoplasm. Furthermore, pharmacological attenuation of glycogenolysis and functional depletion of glycogen both significantly reduced the time to glycolytic run-down by ∼33 and 65%, respectively. These findings suggest that type I cell glycogen metabolism allows for the continuation of glycolysis and the maintenance of CB sensory neuronal output in periods of restricted glucose delivery and this may act as a key protective mechanism for the organ during hypoglycaemia. The ability, or otherwise, to preserve energetic status may thus account for variation in the reported capacity of the CB to sense physiological glucose concentrations and may even underlie its function during pathological states associated with augmented CB discharge.
Original languageEnglish
Pages (from-to)4493-4506
Number of pages14
JournalJournal of Physiology
Volume592
Issue number20
DOIs
Publication statusPublished - 15 Oct 2014

Fingerprint

Carotid Body
Glycogen
Glucose
Glycolysis
Hypoglycemia
Glycogen Phosphorylase
Glycogenolysis
Somatotypes
Glycogen Synthase
Fluorescent Antibody Technique
Cytoplasm
Maintenance
Pharmacology
Electrons
Staining and Labeling
Enzymes

Cite this

Holmes, Andrew P. ; Turner, Philip J. ; Carter, Paul ; Leadbeater, Wendy ; Ray, Clare J. ; Hauton, David ; Buckler, Keith J. ; Kumar, Prem. / Glycogen metabolism protects against metabolic insult to preserve carotid body function during glucose deprivation. In: Journal of Physiology. 2014 ; Vol. 592, No. 20. pp. 4493-4506.
@article{7a09f3316cc643528684ee59547d12a6,
title = "Glycogen metabolism protects against metabolic insult to preserve carotid body function during glucose deprivation",
abstract = "The view that the carotid body (CB) type I cells are direct physiological sensors of hypoglycaemia is challenged by the finding that the basal sensory neuronal outflow from the whole organ is unchanged in response to low glucose. The reason for this difference in viewpoint and how the whole CB maintains its metabolic integrity when exposed to low glucose is unknown. Here we show that, in the intact superfused rat CB, basal sensory neuronal activity was sustained during glucose deprivation for 29.1 ± 1.2 min, before irreversible failure following a brief period of excitation. Graded increases in the basal discharge induced by reducing the superfusate  led to proportional decreases in the time to the pre-failure excitation during glucose deprivation which was dependent on a complete run-down in glycolysis and a fall in cellular energy status. A similar ability to withstand prolonged glucose deprivation was observed in isolated type I cells. Electron micrographs and immunofluorescence staining of rat CB sections revealed the presence of glycogen granules and the glycogen conversion enzymes glycogen synthase I and glycogen phosphorylase BB, dispersed throughout the type I cell cytoplasm. Furthermore, pharmacological attenuation of glycogenolysis and functional depletion of glycogen both significantly reduced the time to glycolytic run-down by ∼33 and 65{\%}, respectively. These findings suggest that type I cell glycogen metabolism allows for the continuation of glycolysis and the maintenance of CB sensory neuronal output in periods of restricted glucose delivery and this may act as a key protective mechanism for the organ during hypoglycaemia. The ability, or otherwise, to preserve energetic status may thus account for variation in the reported capacity of the CB to sense physiological glucose concentrations and may even underlie its function during pathological states associated with augmented CB discharge.",
author = "Holmes, {Andrew P.} and Turner, {Philip J.} and Paul Carter and Wendy Leadbeater and Ray, {Clare J.} and David Hauton and Buckler, {Keith J.} and Prem Kumar",
year = "2014",
month = "10",
day = "15",
doi = "10.1113/jphysiol.2014.276105",
language = "English",
volume = "592",
pages = "4493--4506",
journal = "Journal of Physiology",
issn = "0022-3751",
publisher = "Wiley-Blackwell",
number = "20",

}

Glycogen metabolism protects against metabolic insult to preserve carotid body function during glucose deprivation. / Holmes, Andrew P.; Turner, Philip J.; Carter, Paul; Leadbeater, Wendy; Ray, Clare J.; Hauton, David; Buckler, Keith J.; Kumar, Prem.

In: Journal of Physiology, Vol. 592, No. 20, 15.10.2014, p. 4493-4506.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Glycogen metabolism protects against metabolic insult to preserve carotid body function during glucose deprivation

AU - Holmes, Andrew P.

AU - Turner, Philip J.

AU - Carter, Paul

AU - Leadbeater, Wendy

AU - Ray, Clare J.

AU - Hauton, David

AU - Buckler, Keith J.

AU - Kumar, Prem

PY - 2014/10/15

Y1 - 2014/10/15

N2 - The view that the carotid body (CB) type I cells are direct physiological sensors of hypoglycaemia is challenged by the finding that the basal sensory neuronal outflow from the whole organ is unchanged in response to low glucose. The reason for this difference in viewpoint and how the whole CB maintains its metabolic integrity when exposed to low glucose is unknown. Here we show that, in the intact superfused rat CB, basal sensory neuronal activity was sustained during glucose deprivation for 29.1 ± 1.2 min, before irreversible failure following a brief period of excitation. Graded increases in the basal discharge induced by reducing the superfusate  led to proportional decreases in the time to the pre-failure excitation during glucose deprivation which was dependent on a complete run-down in glycolysis and a fall in cellular energy status. A similar ability to withstand prolonged glucose deprivation was observed in isolated type I cells. Electron micrographs and immunofluorescence staining of rat CB sections revealed the presence of glycogen granules and the glycogen conversion enzymes glycogen synthase I and glycogen phosphorylase BB, dispersed throughout the type I cell cytoplasm. Furthermore, pharmacological attenuation of glycogenolysis and functional depletion of glycogen both significantly reduced the time to glycolytic run-down by ∼33 and 65%, respectively. These findings suggest that type I cell glycogen metabolism allows for the continuation of glycolysis and the maintenance of CB sensory neuronal output in periods of restricted glucose delivery and this may act as a key protective mechanism for the organ during hypoglycaemia. The ability, or otherwise, to preserve energetic status may thus account for variation in the reported capacity of the CB to sense physiological glucose concentrations and may even underlie its function during pathological states associated with augmented CB discharge.

AB - The view that the carotid body (CB) type I cells are direct physiological sensors of hypoglycaemia is challenged by the finding that the basal sensory neuronal outflow from the whole organ is unchanged in response to low glucose. The reason for this difference in viewpoint and how the whole CB maintains its metabolic integrity when exposed to low glucose is unknown. Here we show that, in the intact superfused rat CB, basal sensory neuronal activity was sustained during glucose deprivation for 29.1 ± 1.2 min, before irreversible failure following a brief period of excitation. Graded increases in the basal discharge induced by reducing the superfusate  led to proportional decreases in the time to the pre-failure excitation during glucose deprivation which was dependent on a complete run-down in glycolysis and a fall in cellular energy status. A similar ability to withstand prolonged glucose deprivation was observed in isolated type I cells. Electron micrographs and immunofluorescence staining of rat CB sections revealed the presence of glycogen granules and the glycogen conversion enzymes glycogen synthase I and glycogen phosphorylase BB, dispersed throughout the type I cell cytoplasm. Furthermore, pharmacological attenuation of glycogenolysis and functional depletion of glycogen both significantly reduced the time to glycolytic run-down by ∼33 and 65%, respectively. These findings suggest that type I cell glycogen metabolism allows for the continuation of glycolysis and the maintenance of CB sensory neuronal output in periods of restricted glucose delivery and this may act as a key protective mechanism for the organ during hypoglycaemia. The ability, or otherwise, to preserve energetic status may thus account for variation in the reported capacity of the CB to sense physiological glucose concentrations and may even underlie its function during pathological states associated with augmented CB discharge.

UR - http://www.scopus.com/inward/record.url?scp=84911909854&partnerID=8YFLogxK

UR - https://physoc.onlinelibrary.wiley.com/doi/full/10.1113/jphysiol.2014.276105

U2 - 10.1113/jphysiol.2014.276105

DO - 10.1113/jphysiol.2014.276105

M3 - Article

C2 - 25063821

AN - SCOPUS:84911909854

VL - 592

SP - 4493

EP - 4506

JO - Journal of Physiology

JF - Journal of Physiology

SN - 0022-3751

IS - 20

ER -