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Lactate-Induced Release of GABA in the Ventromedial Hypothalamus Contributes to Counterregulatory Failure in Recurrent Hypoglycemia and Diabetes
Suppression of GABAergic neurotransmission in the ventromedial hypothalamus (VMH) is crucial for full activation of counterregulatory responses to hypoglycemia, and increased γ-aminobutyric acid (GABA) output contributes to counterregulatory failure in recurrently hypoglycemic (RH) and diabetic rats...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837027/ https://www.ncbi.nlm.nih.gov/pubmed/23939392 http://dx.doi.org/10.2337/db13-0770 |
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author | Chan, Owen Paranjape, Sachin A. Horblitt, Adam Zhu, Wanling Sherwin, Robert S. |
author_facet | Chan, Owen Paranjape, Sachin A. Horblitt, Adam Zhu, Wanling Sherwin, Robert S. |
author_sort | Chan, Owen |
collection | PubMed |
description | Suppression of GABAergic neurotransmission in the ventromedial hypothalamus (VMH) is crucial for full activation of counterregulatory responses to hypoglycemia, and increased γ-aminobutyric acid (GABA) output contributes to counterregulatory failure in recurrently hypoglycemic (RH) and diabetic rats. The goal of this study was to establish whether lactate contributes to raising VMH GABA levels in these two conditions. We used microdialysis to deliver artificial extracellular fluid or l-lactate into the VMH and sample for GABA. We then microinjected a GABA(A) receptor antagonist, an inhibitor of lactate transport (4CIN), or an inhibitor of lactate dehydrogenase, oxamate (OX), into the VMH prior to inducing hypoglycemia. To assess whether lactate contributes to raising GABA in RH and diabetes, we injected 4CIN or OX into the VMH of RH and diabetic rats before inducing hypoglycemia. l-lactate raised VMH GABA levels and suppressed counterregulatory responses to hypoglycemia. While blocking GABA(A) receptors did not prevent the lactate-induced rise in GABA, inhibition of lactate transport or utilization did, despite the presence of lactate. All three treatments restored the counterregulatory responses, suggesting that lactate suppresses these responses by enhancing GABA release. Both RH and diabetic rats had higher baseline GABA levels and were unable to reduce GABA levels sufficiently to fully activate counterregulatory responses during hypoglycemia. 4CIN or OX lowered VMH GABA levels in both RH and diabetic rats and restored the counterregulatory responses. Lactate likely contributes to counterregulatory failure in RH and diabetes by increasing VMH GABA levels. |
format | Online Article Text |
id | pubmed-3837027 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-38370272014-12-01 Lactate-Induced Release of GABA in the Ventromedial Hypothalamus Contributes to Counterregulatory Failure in Recurrent Hypoglycemia and Diabetes Chan, Owen Paranjape, Sachin A. Horblitt, Adam Zhu, Wanling Sherwin, Robert S. Diabetes Original Research Suppression of GABAergic neurotransmission in the ventromedial hypothalamus (VMH) is crucial for full activation of counterregulatory responses to hypoglycemia, and increased γ-aminobutyric acid (GABA) output contributes to counterregulatory failure in recurrently hypoglycemic (RH) and diabetic rats. The goal of this study was to establish whether lactate contributes to raising VMH GABA levels in these two conditions. We used microdialysis to deliver artificial extracellular fluid or l-lactate into the VMH and sample for GABA. We then microinjected a GABA(A) receptor antagonist, an inhibitor of lactate transport (4CIN), or an inhibitor of lactate dehydrogenase, oxamate (OX), into the VMH prior to inducing hypoglycemia. To assess whether lactate contributes to raising GABA in RH and diabetes, we injected 4CIN or OX into the VMH of RH and diabetic rats before inducing hypoglycemia. l-lactate raised VMH GABA levels and suppressed counterregulatory responses to hypoglycemia. While blocking GABA(A) receptors did not prevent the lactate-induced rise in GABA, inhibition of lactate transport or utilization did, despite the presence of lactate. All three treatments restored the counterregulatory responses, suggesting that lactate suppresses these responses by enhancing GABA release. Both RH and diabetic rats had higher baseline GABA levels and were unable to reduce GABA levels sufficiently to fully activate counterregulatory responses during hypoglycemia. 4CIN or OX lowered VMH GABA levels in both RH and diabetic rats and restored the counterregulatory responses. Lactate likely contributes to counterregulatory failure in RH and diabetes by increasing VMH GABA levels. American Diabetes Association 2013-12 2013-11-16 /pmc/articles/PMC3837027/ /pubmed/23939392 http://dx.doi.org/10.2337/db13-0770 Text en © 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. |
spellingShingle | Original Research Chan, Owen Paranjape, Sachin A. Horblitt, Adam Zhu, Wanling Sherwin, Robert S. Lactate-Induced Release of GABA in the Ventromedial Hypothalamus Contributes to Counterregulatory Failure in Recurrent Hypoglycemia and Diabetes |
title | Lactate-Induced Release of GABA in the Ventromedial Hypothalamus Contributes to Counterregulatory Failure in Recurrent Hypoglycemia and Diabetes |
title_full | Lactate-Induced Release of GABA in the Ventromedial Hypothalamus Contributes to Counterregulatory Failure in Recurrent Hypoglycemia and Diabetes |
title_fullStr | Lactate-Induced Release of GABA in the Ventromedial Hypothalamus Contributes to Counterregulatory Failure in Recurrent Hypoglycemia and Diabetes |
title_full_unstemmed | Lactate-Induced Release of GABA in the Ventromedial Hypothalamus Contributes to Counterregulatory Failure in Recurrent Hypoglycemia and Diabetes |
title_short | Lactate-Induced Release of GABA in the Ventromedial Hypothalamus Contributes to Counterregulatory Failure in Recurrent Hypoglycemia and Diabetes |
title_sort | lactate-induced release of gaba in the ventromedial hypothalamus contributes to counterregulatory failure in recurrent hypoglycemia and diabetes |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837027/ https://www.ncbi.nlm.nih.gov/pubmed/23939392 http://dx.doi.org/10.2337/db13-0770 |
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