Department of Pharmacology and Physiology, New Jersey Medical School, Newark, New Jersey, United States of America.
PLoS One. 2013 Jul 19;8(7):e68709. doi: 10.1371/journal.pone.0068709. Print 2013.
Hypoglycemia is a severe side effect of intensive insulin therapy. Recurrent hypoglycemia (RH) impairs the counter-regulatory response (CRR) which restores euglycemia. During hypoglycemia, ventromedial hypothalamus (VMH) production of nitric oxide (NO) and activation of its receptor soluble guanylyl cyclase (sGC) are critical for the CRR. Hypoglycemia also increases brain reactive oxygen species (ROS) production. NO production in the presence of ROS causes protein S-nitrosylation. S-nitrosylation of sGC impairs its function and induces desensitization to NO. We hypothesized that during hypoglycemia, the interaction between NO and ROS increases VMH sGC S-nitrosylation levels and impairs the CRR to subsequent episodes of hypoglycemia. VMH ROS production and S-nitrosylation were quantified following three consecutive daily episodes of insulin-hypoglycemia (RH model). The CRR was evaluated in rats in response to acute insulin-induced hypoglycemia or via hypoglycemic-hyperinsulinemic clamps. Pretreatment with the anti-oxidant N-acetyl-cysteine (NAC) was used to prevent increased VMH S-nitrosylation.
Acute insulin-hypoglycemia increased VMH ROS levels by 49±6.3%. RH increased VMH sGC S-nitrosylation. Increasing VMH S-nitrosylation with intracerebroventricular injection of the nitrosylating agent S-nitroso-L-cysteine (CSNO) was associated with decreased glucagon secretion during hypoglycemic clamp. Finally, in RH rats pre-treated with NAC (0.5% in drinking water for 9 days) hypoglycemia-induced VMH ROS production was prevented and glucagon and epinephrine production was not blunted in response to subsequent insulin-hypoglycemia.
These data suggest that NAC may be clinically useful in preventing impaired CRR in patients undergoing intensive-insulin therapy.
低血糖是强化胰岛素治疗的严重副作用。反复发生的低血糖（RH）会损害恢复正常血糖的代偿性反应（CRR）。在低血糖期间，腹内侧下丘脑（VMH）产生的一氧化氮（NO）和激活其受体可溶性鸟苷酸环化酶（sGC）对于 CRR 至关重要。低血糖还会增加大脑内活性氧（ROS）的产生。ROS 存在下的 NO 产生会导致蛋白质 S-亚硝基化。sGC 的 S-亚硝基化会损害其功能，并导致对 NO 的脱敏。我们假设，在低血糖期间，NO 和 ROS 之间的相互作用会增加 VMH sGC 的 S-亚硝基化水平，并损害对随后低血糖发作的 CRR。在胰岛素-低血糖（RH 模型）连续三天发作后，对 VMH ROS 产生和 S-亚硝基化进行了量化。通过急性胰岛素诱导的低血糖或通过低血糖-高胰岛素钳夹来评估 CRR。使用抗氧化剂 N-乙酰半胱氨酸（NAC）预处理可防止 VMH S-亚硝基化增加。
急性胰岛素低血糖使 VMH ROS 水平增加了 49±6.3%。RH 增加了 VMH sGC 的 S-亚硝基化。通过向脑室内注射亚硝化剂 S-亚硝基-L-半胱氨酸（CSNO）增加 VMH S-亚硝基化，与低血糖钳夹期间胰高血糖素分泌减少有关。最后，在 NAC（9 天饮用水中 0.5%）预处理的 RH 大鼠中，低血糖诱导的 VMH ROS 产生得到了预防，并且对随后的胰岛素低血糖反应，胰高血糖素和肾上腺素的产生没有减弱。
这些数据表明，NAC 可能在预防接受强化胰岛素治疗的患者 CRR 受损方面具有临床应用价值。
