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Increased GABAergic Output in the Ventromedial Hypothalamus Contributes to Impaired Hypoglycemic Counterregulation in Diabetic Rats

OBJECTIVE: Impaired glucose counterregulation during hypoglycemia is well documented in patients with type 1 diabetes; however, the molecular mechanisms underlying this defect remain uncertain. We reported that the inhibitory neurotransmitter γ-aminobutyric acid (GABA), in a crucial glucose-sensing...

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Autores principales: Chan, Owen, Paranjape, Sachin, Czyzyk, Daniel, Horblitt, Adam, Zhu, Wanling, Ding, Yuyan, Fan, Xiaoning, Seashore, Margretta, Sherwin, Robert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292334/
https://www.ncbi.nlm.nih.gov/pubmed/21411513
http://dx.doi.org/10.2337/db10-1579
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author Chan, Owen
Paranjape, Sachin
Czyzyk, Daniel
Horblitt, Adam
Zhu, Wanling
Ding, Yuyan
Fan, Xiaoning
Seashore, Margretta
Sherwin, Robert
author_facet Chan, Owen
Paranjape, Sachin
Czyzyk, Daniel
Horblitt, Adam
Zhu, Wanling
Ding, Yuyan
Fan, Xiaoning
Seashore, Margretta
Sherwin, Robert
author_sort Chan, Owen
collection PubMed
description OBJECTIVE: Impaired glucose counterregulation during hypoglycemia is well documented in patients with type 1 diabetes; however, the molecular mechanisms underlying this defect remain uncertain. We reported that the inhibitory neurotransmitter γ-aminobutyric acid (GABA), in a crucial glucose-sensing region within the brain, the ventromedial hypothalamus (VMH), plays an important role in modulating the magnitude of the glucagon and epinephrine responses to hypoglycemia and investigated whether VMH GABAergic tone is altered in diabetes and therefore might contribute to defective counterregulatory responses. RESEARCH DESIGN AND METHODS: We used immunoblots to measure GAD(65) protein (a rate-limiting enzyme in GABA synthesis) and microdialysis to measure extracellular GABA levels in the VMH of two diabetic rat models, the diabetic BB rat and the streptozotocin (STZ)-induced diabetic rat, and compared them with nondiabetic controls. RESULTS: Both diabetic rat models exhibited an ~50% increase in GAD(65) protein as well as a twofold increase in VMH GABA levels compared with controls under baseline conditions. Moreover, during hypoglycemia, VMH GABA levels did not change in the diabetic animals, whereas they significantly declined in nondiabetic animals. As expected, glucagon responses were absent and epinephrine responses were attenuated in diabetic rats compared with their nondiabetic control counterparts. The defective counterregulatory response in STZ-diabetic animals was restored to normal with either local blockade of GABA(A) receptors or knockdown of GAD(65) in the VMH. CONCLUSIONS: These data suggest that increased VMH GABAergic inhibition is an important contributor to the absent glucagon response to hypoglycemia and the development of counterregulatory failure in type 1 diabetes.
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spelling pubmed-32923342012-05-01 Increased GABAergic Output in the Ventromedial Hypothalamus Contributes to Impaired Hypoglycemic Counterregulation in Diabetic Rats Chan, Owen Paranjape, Sachin Czyzyk, Daniel Horblitt, Adam Zhu, Wanling Ding, Yuyan Fan, Xiaoning Seashore, Margretta Sherwin, Robert Diabetes Complications OBJECTIVE: Impaired glucose counterregulation during hypoglycemia is well documented in patients with type 1 diabetes; however, the molecular mechanisms underlying this defect remain uncertain. We reported that the inhibitory neurotransmitter γ-aminobutyric acid (GABA), in a crucial glucose-sensing region within the brain, the ventromedial hypothalamus (VMH), plays an important role in modulating the magnitude of the glucagon and epinephrine responses to hypoglycemia and investigated whether VMH GABAergic tone is altered in diabetes and therefore might contribute to defective counterregulatory responses. RESEARCH DESIGN AND METHODS: We used immunoblots to measure GAD(65) protein (a rate-limiting enzyme in GABA synthesis) and microdialysis to measure extracellular GABA levels in the VMH of two diabetic rat models, the diabetic BB rat and the streptozotocin (STZ)-induced diabetic rat, and compared them with nondiabetic controls. RESULTS: Both diabetic rat models exhibited an ~50% increase in GAD(65) protein as well as a twofold increase in VMH GABA levels compared with controls under baseline conditions. Moreover, during hypoglycemia, VMH GABA levels did not change in the diabetic animals, whereas they significantly declined in nondiabetic animals. As expected, glucagon responses were absent and epinephrine responses were attenuated in diabetic rats compared with their nondiabetic control counterparts. The defective counterregulatory response in STZ-diabetic animals was restored to normal with either local blockade of GABA(A) receptors or knockdown of GAD(65) in the VMH. CONCLUSIONS: These data suggest that increased VMH GABAergic inhibition is an important contributor to the absent glucagon response to hypoglycemia and the development of counterregulatory failure in type 1 diabetes. American Diabetes Association 2011-05 2011-04-23 /pmc/articles/PMC3292334/ /pubmed/21411513 http://dx.doi.org/10.2337/db10-1579 Text en © 2011 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 Complications
Chan, Owen
Paranjape, Sachin
Czyzyk, Daniel
Horblitt, Adam
Zhu, Wanling
Ding, Yuyan
Fan, Xiaoning
Seashore, Margretta
Sherwin, Robert
Increased GABAergic Output in the Ventromedial Hypothalamus Contributes to Impaired Hypoglycemic Counterregulation in Diabetic Rats
title Increased GABAergic Output in the Ventromedial Hypothalamus Contributes to Impaired Hypoglycemic Counterregulation in Diabetic Rats
title_full Increased GABAergic Output in the Ventromedial Hypothalamus Contributes to Impaired Hypoglycemic Counterregulation in Diabetic Rats
title_fullStr Increased GABAergic Output in the Ventromedial Hypothalamus Contributes to Impaired Hypoglycemic Counterregulation in Diabetic Rats
title_full_unstemmed Increased GABAergic Output in the Ventromedial Hypothalamus Contributes to Impaired Hypoglycemic Counterregulation in Diabetic Rats
title_short Increased GABAergic Output in the Ventromedial Hypothalamus Contributes to Impaired Hypoglycemic Counterregulation in Diabetic Rats
title_sort increased gabaergic output in the ventromedial hypothalamus contributes to impaired hypoglycemic counterregulation in diabetic rats
topic Complications
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292334/
https://www.ncbi.nlm.nih.gov/pubmed/21411513
http://dx.doi.org/10.2337/db10-1579
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