Vitamin C (VC, -ascorbic acid) is an essential nutrient that plays a key role in metabolism and functions as a potent antioxidant in regulating the S-nitrosylation and denitrosylation of target proteins. The precise function of VC deprivation in glucose homeostasis is still unknown. In the absence of L-gulono-1,4-lactone oxidoreductase, an essential enzyme for the last step of VC synthesis, VC deprivation resulted in persistent hypoglycemia and subsequent impairment of cognitive functions in female but not male mouse pups. The cognitive disorders caused by VC deprivation were largely reversed when these female pups were given glucose. VC deprivation-induced S-nitrosylation of glycogen synthase kinase 3β (GSK3β) at Cys14, which activated GSK3β and inactivated glycogen synthase to decrease glycogen synthesis and storage under the feeding condition, while VC deprivation inactivated glycogen phosphorylase to decrease glycogenolysis under the fasting condition, ultimately leading to hypoglycemia and cognitive disorders. Treatment with Nω-Nitro--arginine methyl ester (-NAME), a specific inhibitor of nitric oxide synthase, on the other hand, effectively prevented S-nitrosylation and activation of GSK3β in female pups in response to the VC deprivation and reversed hypoglycemia and cognitive disorders. Overall, this research identifies S-nitrosylation of GSK3β and subsequent GSK3β activation as a previously unknown mechanism controlling glucose homeostasis in female pups in response to VC deprivation, implying that VC supplementation in the prevention of hypoglycemia and cognitive disorders should be considered in the certain groups of people, particularly young females.

中文翻译：

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维生素 C 缺乏通过 S-亚硝基化介导的糖原合酶激酶 3β 激活诱发低血糖和认知障碍

维生素 C（VC，-抗坏血酸）是一种必需营养素，在新陈代谢中发挥着关键作用，并作为有效的抗氧化剂调节目标蛋白的 S-亚硝基化和脱亚硝基化。 VC 剥夺在葡萄糖稳态中的确切功能仍不清楚。在缺乏 L-古洛糖酸-1,4-内酯氧化还原酶（VC 合成最后一步的必需酶）的情况下，VC 剥夺会导致雌性幼鼠（而非雄性幼鼠）持续低血糖，并随后导致认知功能受损。当给这些雌性幼崽喂食葡萄糖后，因维生素C剥夺而引起的认知障碍在很大程度上得到了逆转。 VC剥夺诱导糖原合酶激酶3β（GSK3β）在Cys14处的S-亚硝基化，激活GSK3β并灭活糖原合酶，以减少进食条件下的糖原合成和储存，而VC剥夺则灭活糖原磷酸化酶以减少空腹条件下的糖原分解，最终导致低血糖和认知障碍。另一方面，用一氧化氮合酶的特异性抑制剂 Nω-硝基-精氨酸甲酯 (-NAME) 治疗，可有效防止雌性幼崽响应 VC 剥夺而发生的 S-亚硝基化和 GSK3β 激活，并逆转低血糖和认知障碍。总体而言，这项研究确定了 GSK3β 的 S-亚硝基化和随后的 GSK3β 激活是一种先前未知的机制，可控制雌性幼崽响应 VC 剥夺的葡萄糖稳态，这意味着某些群体应考虑补充 VC 来预防低血糖和认知障碍的人，尤其是年轻女性。