School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, United States.
School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, United States.
Brain Res Bull. 2020 Apr;157:41-50. doi: 10.1016/j.brainresbull.2020.01.013. Epub 2020 Jan 22.
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 alpha-adrenergic receptor (α-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 α-AR - dependent up-regulated GLT and α-AR profiles, while GABA cells showed down-regulated α-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 α-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 α-AR - mediated up-regulated pyruvate recycling.
目前尚不清楚代谢传感器对反复胰岛素诱导的低血糖（RIIH）适应的机制。去甲肾上腺素（NE）调节腹内侧下丘脑核（VMN）的葡萄糖刺激型一氧化氮（NO）和葡萄糖抑制型γ-氨基丁酸（GABA）神经元信号。目前的研究假设，在 RIIH 期间，NE 抑制两群神经元中 5'-AMP 激活蛋白激酶（AMPK）的反应性，并阻碍代偿反应。据推测，大脑在低血糖期间会利用非葡萄糖底物，例如氨基酸谷氨酰胺（Gln）、谷氨酸（Glu）和天冬氨酸（Asp），来产生能量。一个相关的目标是研究 NE 是否控制代谢-感觉细胞群体中丙酮酸循环途径标记蛋白（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 天通过脑室注射α-肾上腺素受体（α-AR）反向激动剂普萘洛尔（PRZ）或载体进行预处理，然后进行最后一次胰岛素治疗。PRZ 可防止急性低血糖时 AMPK 在每组细胞中的激活增加。PRZ 逆转了 GABA 神经元中传感器活性的先前低血糖抑制。在 RIIH 期间，氮能神经元表现出依赖于α-AR 的 GLT 和 α-AR 谱上调，而 GABA 细胞显示α-AR 下调。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，以及前两种谱型对 RIIH 的适应。PRZ 减弱了急性低血糖时胰高血糖素和皮质酮的分泌，但逆转了 RIIH 期间这两种激素分泌的减少。结果表明，在 RIIH 期间，VMN 代谢感觉 AMPK 激活和代偿功能障碍的抑制中，α-AR 信号的影响发生了调整。先前的低血糖可能通过 α-AR 介导的丙酮酸循环上调来增加 NO 神经元的能量产量。
