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Changes in pyruvate dehydrogenase complex activity during and following severe insulin-induced hypoglycemia

Cardell, M. LU ; Siesjo, B. K. and Wieloch, T. LU (1991) In Journal of Cerebral Blood Flow and Metabolism 11(1). p.122-128
Abstract

The effect of severe insulin-induced hypoglycemia on the activity of the pyruvate dehydrogenase enzyme complex (PDHC) was investigated in homogenates of frozen rat cerebral cortex during burst suppression EEG, after 10, 30, and 60 min of isoelectric EEG, and after 30 and 180 min and 24 h of recovery following 30 min of hypoglycemic coma. Changes in PDHC activity were correlated to levels of labile organic phosphates and glycolytic metabolites. In cortex from control animals, the rate of [1-14C]pyruvate decarboxylation was 7.1 ± 1.3 U/mg of protein, or 35% of the total PDHC activity. The activity was unchanged during burst suppression EEG whereas the active fraction increased to 81-87% during hypoglycemic coma. Thirty minutes... (More)

The effect of severe insulin-induced hypoglycemia on the activity of the pyruvate dehydrogenase enzyme complex (PDHC) was investigated in homogenates of frozen rat cerebral cortex during burst suppression EEG, after 10, 30, and 60 min of isoelectric EEG, and after 30 and 180 min and 24 h of recovery following 30 min of hypoglycemic coma. Changes in PDHC activity were correlated to levels of labile organic phosphates and glycolytic metabolites. In cortex from control animals, the rate of [1-14C]pyruvate decarboxylation was 7.1 ± 1.3 U/mg of protein, or 35% of the total PDHC activity. The activity was unchanged during burst suppression EEG whereas the active fraction increased to 81-87% during hypoglycemic coma. Thirty minutes after glucose-induced recovery, the PDHC activity had decreased by 33% compared to control levels, and remained significantly depressed after 3 h of recovery. This decrease in activity was not due to a decrease in the total PDHC activity. At 24 h of recovery, PDHC activity had returned to control levels. We conclude that the activation of PDHC during hypoglycemic coma is probably the result of an increased PDH phosphatase activity following depolarization and calcium influx, and allosteric inhibition of PDH kinase due to increased ADP/ATP ratio. The depression of PDHC activity following hypoglycemic coma is probably due to an increased phosphorylation of the enzyme, as a consequence of an imbalance between PDH phosphatase and kinase activities. Since some reduction of the ATP/ADP ratio persisted and since the lactate pyruvate ratio had normalized by 3 h of recovery, the depression of PDHC most likely reflects a decrease in PDH phosphatase activity, probably due to a decrease in intramitochondrial Ca2+.

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author
; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Calcium, Energy metabolism, Hypoglycemia, Mitochondria, Pyruvate dehydrogenase complex
in
Journal of Cerebral Blood Flow and Metabolism
volume
11
issue
1
pages
7 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:1983996
  • scopus:0026025708
ISSN
0271-678X
DOI
10.1038/jcbfm.1991.14
language
English
LU publication?
yes
id
ce053813-2b98-45e0-a219-d1edcd52a7e1
date added to LUP
2019-06-13 16:26:58
date last changed
2024-01-01 10:20:51
@article{ce053813-2b98-45e0-a219-d1edcd52a7e1,
  abstract     = {{<p>The effect of severe insulin-induced hypoglycemia on the activity of the pyruvate dehydrogenase enzyme complex (PDHC) was investigated in homogenates of frozen rat cerebral cortex during burst suppression EEG, after 10, 30, and 60 min of isoelectric EEG, and after 30 and 180 min and 24 h of recovery following 30 min of hypoglycemic coma. Changes in PDHC activity were correlated to levels of labile organic phosphates and glycolytic metabolites. In cortex from control animals, the rate of [1-<sup>14</sup>C]pyruvate decarboxylation was 7.1 ± 1.3 U/mg of protein, or 35% of the total PDHC activity. The activity was unchanged during burst suppression EEG whereas the active fraction increased to 81-87% during hypoglycemic coma. Thirty minutes after glucose-induced recovery, the PDHC activity had decreased by 33% compared to control levels, and remained significantly depressed after 3 h of recovery. This decrease in activity was not due to a decrease in the total PDHC activity. At 24 h of recovery, PDHC activity had returned to control levels. We conclude that the activation of PDHC during hypoglycemic coma is probably the result of an increased PDH phosphatase activity following depolarization and calcium influx, and allosteric inhibition of PDH kinase due to increased ADP/ATP ratio. The depression of PDHC activity following hypoglycemic coma is probably due to an increased phosphorylation of the enzyme, as a consequence of an imbalance between PDH phosphatase and kinase activities. Since some reduction of the ATP/ADP ratio persisted and since the lactate pyruvate ratio had normalized by 3 h of recovery, the depression of PDHC most likely reflects a decrease in PDH phosphatase activity, probably due to a decrease in intramitochondrial Ca<sup>2+</sup>.</p>}},
  author       = {{Cardell, M. and Siesjo, B. K. and Wieloch, T.}},
  issn         = {{0271-678X}},
  keywords     = {{Calcium; Energy metabolism; Hypoglycemia; Mitochondria; Pyruvate dehydrogenase complex}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{1}},
  pages        = {{122--128}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Journal of Cerebral Blood Flow and Metabolism}},
  title        = {{Changes in pyruvate dehydrogenase complex activity during and following severe insulin-induced hypoglycemia}},
  url          = {{http://dx.doi.org/10.1038/jcbfm.1991.14}},
  doi          = {{10.1038/jcbfm.1991.14}},
  volume       = {{11}},
  year         = {{1991}},
}