title: High Glucose-Induced PC12 Cell Death by Increasing Glutamate Production and Decreasing Methyl Group Metabolism.
abstract: Objective. High glucose- (HG-) induced neuronal cell death is responsible for the development of diabetic neuropathy. However, the effect of HG on metabolism in neuronal cells is still unclear. Materials and Methods. The neural-crest derived PC12 cells were cultured for 72 h in the HG (75 mM) or control (25 mM) groups. We used NMR-based metabolomics to examine both intracellular and extracellular metabolic changes in HG-treated PC12 cells. Results. We found that the reduction in intracellular lactate may be due to excreting more lactate into the extracellular medium under HG condition. HG also induced the changes of other energy-related metabolites, such as an increased succinate and creatine phosphate. Our results also reveal that the synthesis of glutamate from the branched-chain amino acids (isoleucine and valine) may be enhanced under HG. Increased levels of intracellular alanine, phenylalanine, myoinositol, and choline were observed in HG-treated PC12 cells. In addition, HG-induced decreases in intracellular dimethylamine, dimethylglycine, and 3-methylhistidine may indicate a downregulation of methyl group metabolism. Conclusions. Our metabolomic results suggest that HG-induced neuronal cell death may be attributed to a series of metabolic changes, involving energy metabolism, amino acids metabolism, osmoregulation and membrane metabolism, and methyl group metabolism.
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China; Lishui Central Hospital, The Fifth Affiliated Hospital, Wenzhou Medical University, Lishui 323000, China.
authors.forename: Minjiang
authors.initials: M
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Wei
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Xia
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Liangcai
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Lishui Central Hospital, The Fifth Affiliated Hospital, Wenzhou Medical University, Lishui 323000, China.
authors.forename: Jiansong
authors.initials: J
authors.lastname: Ji
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Hongchang
authors.identifier: 0000-0003-3462-1879
authors.initials: H
authors.lastname: Gao
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D005947:Glucose / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018698:Glutamic Acid / Q000096:biosynthesis*; D006838:Hydrocarbons / Q000378:metabolism*; D055442:Metabolome / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells; D051381:Rats
chemical_list: D000596:Amino Acids; D006838:Hydrocarbons; D018698:Glutamic Acid; D005947:Glucose