Blockade of GABAA receptors in the ventromedial hypothalamus further stimulates glucagon and sympathoadrenal but not the hypothalamo-pituitary-adrenal response to hypoglycemia
Blockade of GABAA receptors in the ventromedial hypothalamus further stimulates glucagon and sympathoadrenal but not the hypothalamo-pituitary-adrenal response to hypoglycemia
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DOI：
10.2337/diabetes.55.04.06.db05-0958
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发表时间：
2006-04-01
期刊：
影响因子：
7.7
通讯作者：
Sherwin, RS
中科院分区：
文献类型：
--
作者：
Chan, O;Zhu, WL;Sherwin, RS
低血糖引起多方面的逆调节反应，涉及交感-肾上腺系统、高血糖素分泌的刺激以及糖尿病患者常见的下丘脑-垂体-肾上腺轴。我们研究了伽马氨基丁酸(GABA)对下丘脑腹内侧(VMH)的抑制输入的调制是否在影响对低血糖的反调节反应中发挥作用。VMH是大脑中主要的葡萄糖敏感区。正常SD大鼠长期植入颈动脉和颈静脉导管，并将双侧钢质微量注射导管插入VMH水平。术后7~10d，显微注射GABA(A)受体激动剂Muscimol(1nmol/侧)或GABA(A)受体拮抗剂荷包牡丹碱(12.5pmol/侧)，然后给予高胰岛素-低血糖(2.5 mm o l/L)葡萄糖钳夹90min。与对照组相比，VMH注射荷包牡丹碱后，葡萄糖输注速率显著降低，而蝇草酚显著增加葡萄糖输注速率。与对照组相比，使用拮抗剂时，高血糖素和肾上腺素的反应升高，而使用激动剂时，则受到抑制。然而，向VMH内注入激动剂或拮抗剂均不影响皮质酮反应。这些数据表明，VMH中GABA能系统的调节改变了胰高血糖素和交感肾上腺，但不改变皮质酮对低血糖的反应。我们的发现与这一假说是一致的，即VMH内的GABA能抑制音可以调节葡萄糖的反调节反应。
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 GABAA 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.