Vitamin C deficiency induces hypoglycemia and cognitive disorder through S-nitrosylation-mediated activation of glycogen synthase kinase 3β
Yingying Shu,
Chaochun Zou,
Yuqing Cai,
Qiangqiang He,
Xiaowei Wu,
Haibin Zhu,
Meiyu Qv,
Yunqi Chao,
Chengyun Xu,
Lanfang Tang,
Ximei Wu
Affiliations
Yingying Shu
Department of Endocrinology, The Children's Hospital of Zhejiang University School of Medicine, Hangzhou, 310053, China; National Clinical Research Center for Child Health, The Children's Hospital of Zhejiang University School of Medicine, Hangzhou, 310053, China
Chaochun Zou
Department of Endocrinology, The Children's Hospital of Zhejiang University School of Medicine, Hangzhou, 310053, China; National Clinical Research Center for Child Health, The Children's Hospital of Zhejiang University School of Medicine, Hangzhou, 310053, China; Corresponding author. Department of Endocrinology, The Children's Hospital of Zhejiang University School of Medicine, 3333 Binsheng Road, Hangzhou, 310053, China.
Yuqing Cai
Department of Endocrinology, The Children's Hospital of Zhejiang University School of Medicine, Hangzhou, 310053, China; National Clinical Research Center for Child Health, The Children's Hospital of Zhejiang University School of Medicine, Hangzhou, 310053, China
Qiangqiang He
Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, 310058, China
Xiaowei Wu
Department of Obstetrics and Gynecology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
Haibin Zhu
Department of Obstetrics and Gynecology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
Meiyu Qv
Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, 310058, China
Yunqi Chao
Department of Endocrinology, The Children's Hospital of Zhejiang University School of Medicine, Hangzhou, 310053, China; National Clinical Research Center for Child Health, The Children's Hospital of Zhejiang University School of Medicine, Hangzhou, 310053, China
Chengyun Xu
National Clinical Research Center for Child Health, The Children's Hospital of Zhejiang University School of Medicine, Hangzhou, 310053, China; Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, 310058, China
Lanfang Tang
National Clinical Research Center for Child Health, The Children's Hospital of Zhejiang University School of Medicine, Hangzhou, 310053, China
Ximei Wu
Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, 310058, China; Corresponding author. Department of Pharmacology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China.
Vitamin C (VC, l-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-l-arginine methyl ester (l-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.
