Mechanisms that underlie metabolic sensor acclimation to recurring insulin-induced hypoglycemia (RIIH) are unclear. Norepinephrine (NE) regulates ventromedial hypothalamic nucleus (VMN) gluco-stimulatory nitric oxide (NO) and gluco-inhibitory γ-aminobutryic acid (GABA) neuron signaling. Current research addressed the hypothesis that during RIIH, NE suppresses 5'-AMP-activated protein kinase (AMPK) reactivity in both populations and impedes counter-regulation. The brain is postulated to utilize non-glucose substrates, e.g. amino acids glutamine (Gln), glutamate (Glu), and aspartate (Asp), to produce energy during hypoglycemia. A correlated aim investigated whether NE controls pyruvate recycling pathway marker protein (glutaminase, GLT; malic enzyme, ME-1) expression in either metabolic-sensory cell population. Male rats were injected subcutaneously with vehicle or insulin on days 1-3, then pretreated on day 4 by intracerebroventricular delivery of the alpha1-adrenergic receptor (α1-AR) reverse-agonist prazocin (PRZ) or vehicle before final insulin therapy. PRZ prevented acute hypoglycemic augmentation of AMPK activation in each cell group. Antecedent hypoglycemic repression of sensor activity was reversed by PRZ in GABA neurons. During RIIH, nitrergic neurons exhibited α1-AR - dependent up-regulated GLT and α2-AR profiles, while GABA cells showed down-regulated α1-AR. LC-ESI-MS analysis documented a decline in VMN Glu, Gln, and Asp concentrations during acute hypoglycemia, and habituation of the former two profiles to RIIH. PRZ attenuated glucagon and corticosterone secretion during acute hypoglycemia, but reversed decrements in output of both hormones during RIIH. Results implicate adjustments in impact of α1-AR signaling in repressed VMN metabolic-sensory AMPK activation and counter-regulatory dysfunction during RIIH. Antecedent hypoglycemia may up-regulate NO neuron energy yield via α1-AR - mediated up-regulated pyruvate recycling.

中文翻译：

---

急性与复发性胰岛素诱导的低血糖对腹内侧下丘脑核代谢感觉神经元 AMPK 活性的影响：α1-肾上腺素能受体信号传导的影响。

代谢传感器适应复发性胰岛素诱导低血糖 (RIIH) 的机制尚不清楚。去甲肾上腺素 (NE) 调节腹内侧下丘脑核 (VMN) 葡萄糖刺激性一氧化氮 (NO) 和葡萄糖抑制性 γ-氨基丁酸 (GABA) 神经元信号。当前的研究解决了在 RIIH 期间，NE 抑制 5'-AMP 活化蛋白激酶 (AMPK) 在两个人群中的反应性并阻碍反调节的假设。大脑被假定利用非葡萄糖底物，例如氨基酸谷氨酰胺 (Gln)、谷氨酸 (Glu) 和天冬氨酸 (Asp)，在低血糖期间产生能量。一个相关的目的是研究 NE 是否控制任一代谢感觉细胞群中丙酮酸再循环途径标记蛋白（谷氨酰胺酶，GLT；苹果酸酶，ME-1）的表达。雄性大鼠在第 1-3 天皮下注射载体或胰岛素，然后在第 4 天通过脑室内递送 α1-肾上腺素能受体 (α1-AR) 反向激动剂哌唑嗪 (PRZ) 或载体在最终胰岛素治疗前进行预处理。PRZ 可防止每个细胞组中 AMPK 激活的急性低血糖增加。GABA 神经元中的 PRZ 逆转了传感器活动的先前低血糖抑制。在RIIH期间，氮能神经元表现出α1-AR依赖性上调的GLT和α2-AR谱，而GABA细胞表现出下调的α1-AR。LC-ESI-MS 分析记录了急性低血糖期间 VMN Glu、Gln 和 Asp 浓度的下降，以及前两种特征对 RIIH 的习惯化。PRZ 在急性低血糖期间减弱胰高血糖素和皮质酮的分泌，但在 RIIH 期间逆转了两种激素输出的减少。结果表明，α1-AR 信号在 RIIH 期间对受抑制的 VMN 代谢-感觉 AMPK 激活和反调节功能障碍的影响进行了调整。先前的低血糖可能通过 α1-AR 介导的上调丙酮酸再循环来上调 NO 神经元能量产量。