Blockade of GABAA receptors in the ventromedial hypothalamus further stimulates glucagon and sympathoadrenal but not the hypothalamo-pituitary-adrenal response to hypoglycemia

Owen Chan, Wanling Zhu, Yuyan Ding, Rory J. McCrimmon, Robert S. Sherwin (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    63 Citations (Scopus)

    Abstract

    Hypoglycemia provokes a multifaceted counterregulatory response involving the sympathoadrenal system, stimulation of glucagon secretion, and the hypothalamo-pituitary-adrenal axis that is commonly impaired in diabetes. We examined whether modulation of inhibitory input from gamma-aminobutyric acid (GABA) in the ventromedial hypothalamus (VMH), a major glucose-sensing region within the brain, plays a role in affecting counterregulatory responses to hypoglycemia. Normal Sprague-Dawley rats had carotid artery and jugular vein catheters chronically implanted, as well as bilateral steel microinjection guide cannulas inserted down to the level of the VMH. Seven to 10 days following surgery, the rats were microinjected with artificial extracellular fluid, the GABA(A) receptor agonist muscimol (1 nmol/side), or the GABA(A) receptor antagonist bicuculline methiodide (12.5 pmol/side) before being subjected to a hyperinsulinemic-hypoglycemic (2.5 mmol/l) glucose clamp for 90 min. Following VMH administration of bicuculline methiodide, glucose infusion rates were significantly suppressed, whereas muscimol raised glucose infusion rates significantly compared with controls. Glucagon and epinephrine responses were elevated with the antagonist and suppressed with the agonist compared with controls. Corticosterone responses, however, were unaffected by either administration of the agonist or antagonist into the VMH. These data demonstrate that modulation of the GABAergic system in the VMH alters both glucagon and sympathoadrenal, but not corticosterone, responses to hypoglycemia. Our findings are consistent with the hypothesis that GABAergic inhibitory tone within the VMH can modulate glucose counterregulatory responses.
    Original languageEnglish
    Pages (from-to)1080-1087
    Number of pages8
    JournalDiabetes
    Volume55
    Issue number4
    DOIs
    Publication statusPublished - Apr 2006

    Fingerprint

    GABA-A Receptors
    Glucagon
    Hypoglycemia
    Hypothalamus
    Glucose
    Muscimol
    GABA Receptors
    Corticosterone
    Glucose Clamp Technique
    Steel
    Extracellular Fluid
    Jugular Veins
    Microinjections
    Ambulatory Surgical Procedures
    Carotid Arteries
    Hypoglycemic Agents
    gamma-Aminobutyric Acid
    Epinephrine
    Sprague Dawley Rats
    Catheters

    Cite this

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    title = "Blockade of GABAA receptors in the ventromedial hypothalamus further stimulates glucagon and sympathoadrenal but not the hypothalamo-pituitary-adrenal response to hypoglycemia",
    abstract = "Hypoglycemia provokes a multifaceted counterregulatory response involving the sympathoadrenal system, stimulation of glucagon secretion, and the hypothalamo-pituitary-adrenal axis that is commonly impaired in diabetes. We examined whether modulation of inhibitory input from gamma-aminobutyric acid (GABA) in the ventromedial hypothalamus (VMH), a major glucose-sensing region within the brain, plays a role in affecting counterregulatory responses to hypoglycemia. Normal Sprague-Dawley rats had carotid artery and jugular vein catheters chronically implanted, as well as bilateral steel microinjection guide cannulas inserted down to the level of the VMH. Seven to 10 days following surgery, the rats were microinjected with artificial extracellular fluid, the GABA(A) receptor agonist muscimol (1 nmol/side), or the GABA(A) receptor antagonist bicuculline methiodide (12.5 pmol/side) before being subjected to a hyperinsulinemic-hypoglycemic (2.5 mmol/l) glucose clamp for 90 min. Following VMH administration of bicuculline methiodide, glucose infusion rates were significantly suppressed, whereas muscimol raised glucose infusion rates significantly compared with controls. Glucagon and epinephrine responses were elevated with the antagonist and suppressed with the agonist compared with controls. Corticosterone responses, however, were unaffected by either administration of the agonist or antagonist into the VMH. These data demonstrate that modulation of the GABAergic system in the VMH alters both glucagon and sympathoadrenal, but not corticosterone, responses to hypoglycemia. Our findings are consistent with the hypothesis that GABAergic inhibitory tone within the VMH can modulate glucose counterregulatory responses.",
    author = "Owen Chan and Wanling Zhu and Yuyan Ding and McCrimmon, {Rory J.} and Sherwin, {Robert S.}",
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    Blockade of GABAA receptors in the ventromedial hypothalamus further stimulates glucagon and sympathoadrenal but not the hypothalamo-pituitary-adrenal response to hypoglycemia. / Chan, Owen; Zhu, Wanling; Ding, Yuyan; McCrimmon, Rory J.; Sherwin, Robert S. (Lead / Corresponding author).

    In: Diabetes, Vol. 55, No. 4, 04.2006, p. 1080-1087.

    Research output: Contribution to journalArticle

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    AU - McCrimmon, Rory J.

    AU - Sherwin, Robert S.

    N1 - M1 - 4 Chan, Owen Zhu, Wanling Ding, Yuyan McCrimmon, Rory J Sherwin, Robert S eng DK20495/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2006/03/29 09:00 Diabetes. 2006 Apr;55(4):1080-7.

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    N2 - Hypoglycemia provokes a multifaceted counterregulatory response involving the sympathoadrenal system, stimulation of glucagon secretion, and the hypothalamo-pituitary-adrenal axis that is commonly impaired in diabetes. We examined whether modulation of inhibitory input from gamma-aminobutyric acid (GABA) in the ventromedial hypothalamus (VMH), a major glucose-sensing region within the brain, plays a role in affecting counterregulatory responses to hypoglycemia. Normal Sprague-Dawley rats had carotid artery and jugular vein catheters chronically implanted, as well as bilateral steel microinjection guide cannulas inserted down to the level of the VMH. Seven to 10 days following surgery, the rats were microinjected with artificial extracellular fluid, the GABA(A) receptor agonist muscimol (1 nmol/side), or the GABA(A) receptor antagonist bicuculline methiodide (12.5 pmol/side) before being subjected to a hyperinsulinemic-hypoglycemic (2.5 mmol/l) glucose clamp for 90 min. Following VMH administration of bicuculline methiodide, glucose infusion rates were significantly suppressed, whereas muscimol raised glucose infusion rates significantly compared with controls. Glucagon and epinephrine responses were elevated with the antagonist and suppressed with the agonist compared with controls. Corticosterone responses, however, were unaffected by either administration of the agonist or antagonist into the VMH. These data demonstrate that modulation of the GABAergic system in the VMH alters both glucagon and sympathoadrenal, but not corticosterone, responses to hypoglycemia. Our findings are consistent with the hypothesis that GABAergic inhibitory tone within the VMH can modulate glucose counterregulatory responses.

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