School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, 356 Bienville Building, 1800 Bienville Drive, Monroe, LA, 71201, USA.
Brain Struct Funct. 2021 May;226(4):1053-1065. doi: 10.1007/s00429-021-02225-8. Epub 2021 Feb 12.
Recurring insulin-induced hypoglycemia (RIIH) in males correlates with maladaptive glucose counter-regulatory collapse and acclimated expression of ventromedial hypothalamic nucleus (VMN) nitric oxide (NO) and γ-aminobutyric acid (GABA) metabolic transmitter biomarkers, e.g., neuronal nitric oxide synthase (nNOS) and glutamate decarboxylase (GAD). Hindbrain noradrenergic neurons innervate the VMN, where norepinephrine regulates nNOS and GAD expression. Current research investigated the hypothesis that antecedent hypoglycemia (AH) exposure causes sex-dimorphic habituation of VMN glucoregulatory biomarker proteins between and/or during serial hypoglycemic bouts, and that hindbrain catecholaminergic (CA) signaling may control sex-specific adaptation of one or more of these proteins. Data show that upon recovery from AH, females exhibit CA-mediated reductions in baseline VMN nNOS, GAD, steroidogenic factor-1 (SF-1), and brain-derived neurotrophic factor (BNDF) expression compared to euglycemic profiles. In males, however, AH caused 6-OHDA-insensitive suppression of only basal SF-1 levels in the VMN. VMN transmitter protein acclimation to RIIH was sex-contingent, as differential nNOS, GAD, SF-1, and BDNF responses to a single vs final bout of hypoglycemia occur in males, whereas females show acclimated reactivity of GAD and SF-1 only to renewed hypoglycemia. CA-mediated and -independent habituation of distinctive VMN protein profiles occurred in each sex. Further research is necessary to evaluate, in each sex, effects of altered baseline VMN metabolic neurotransmitter signals on glucose homeostasis as well as non-metabolic functions under the control of those neurochemicals. It would also be insightful to learn if and how sex-contingent habituation of VMN transmitter responses to hypoglycemia contribute to sex-dimorphic patterns of glucose counter-regulation during RIIH.
男性中反复发作的胰岛素诱导性低血糖 (RIIH) 与葡萄糖代偿性崩溃和适应表达的腹内侧下丘脑核 (VMN) 一氧化氮 (NO) 和 γ-氨基丁酸 (GABA) 代谢递质生物标志物相关，例如神经元型一氧化氮合酶 (nNOS) 和谷氨酸脱羧酶 (GAD)。后脑去甲肾上腺素能神经元支配 VMN，去甲肾上腺素调节 nNOS 和 GAD 的表达。目前的研究假设，先前的低血糖 (AH) 暴露会导致 VMN 糖调节生物标志物蛋白在连续低血糖发作期间和/或之间出现性别二态性适应，并且后脑儿茶酚胺能 (CA) 信号可能控制这些蛋白中的一种或多种的性别特异性适应。数据表明，在从 AH 恢复后，与正常血糖谱相比，女性表现出 CA 介导的 VMN nNOS、GAD、类固醇生成因子-1 (SF-1) 和脑源性神经营养因子 (BDNF) 表达的降低。然而，在男性中，AH 仅导致 VMN 中基础 SF-1 水平的 6-OHDA 不敏感抑制。VMN 递质蛋白对 RIIH 的适应具有性别依赖性，因为在男性中，单一低血糖发作与最后一次低血糖发作相比，nNOS、GAD、SF-1 和 BDNF 的反应不同，而女性仅对重新出现的低血糖表现出 GAD 和 SF-1 的适应反应。在每一种性别中，都存在 CA 介导和独立的 VMN 蛋白特征的适应。需要进一步研究，以评估在每一种性别中，VMN 代谢神经递质信号的基线改变对葡萄糖稳态的影响，以及这些神经化学物质控制下的非代谢功能。了解 VMN 递质对低血糖反应的适应是否以及如何导致 RIIH 期间葡萄糖代偿性反应的性别二态性模式，也将具有启发性。
