High Glucose-Induced PC12 Cell Death by Increasing Glutamate Production and Decreasing Methyl Group Metabolism.

Minjiang Chen,Huanhuan Xia,Hongchang Gao,Jiansong Ji,Hong Zheng,Dan Wang,Liangcai Zhao,Tingting Wei

doi:10.1155/2016/4125731

Minjiang Chen, Huanhuan Xia + Show 6 more

Open Access

https://doi.org/10.1155/2016/4125731

Copy DOI

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.

Highlights

Diabetes mellitus is a group of metabolic disorder diseases affecting an increasing number of the population in the world
Hyperglycemia plays a critical role in the development of diabetic neuropathy, which may be attributed to High glucose- (HG-)induced neuronal cell death [22]
NMRbased metabolomics was used to examine the metabolic changes inside and outside the high glucose (HG)-treated PC12 cells, and the results show that HG-induced neuronal cell death may be associated with the changes of energy metabolism, amino acids metabolism, osmoregulation, and membrane metabolism as well as methyl group metabolism

Summary

Introduction

Diabetes mellitus is a group of metabolic disorder diseases affecting an increasing number of the population in the world. According to survey results from Shaw et al [1], approximately 6.4% of the global adult population suffered from diabetes mellitus in 2010, and this number will increase to 7.7% by 2030. Diabetic neuropathy is the most common microvascular complication of diabetes and more than half of diabetics will develop neuropathy, which affects sensory, motor, and autonomic nerves and results in nontraumatic amputations and autonomic failure [3]. PKC has been shown to play a key role in nerve function and impact the development of diabetic neuropathy [10]. The pathological causes of diabetic neuropathy are increasingly discovered, the potential metabolic mechanism of high glucose-induced toxicity on neuronal cells is still far from being fully understood

Methods

Results

Discussion

Conclusion