Background
Glutamate is a major neurotransmitter, although it causes cytotoxicity and inflammation in nonneuronal organs. This study aimed to investigate the metabolic disorders in which glutamate, associated with type 2 diabetes onset, is induced in the liver.
Conclusions
Increased glutamate is closely associated with the development of diabetes, and it may cause metabolic disorders by inhibiting the fibrinolytic system, which plays an important role in determining blood clots, a hallmark of diabetes. 背景:谷氨酸是一种主要的神经递质, 尽管它在非神经元器官中引起细胞毒性和炎症。本研究旨在探讨与2型糖尿病发病相关的谷氨酸在肝脏中诱导的代谢紊乱。 方法:对韩国基于社区的Ansan-Ansung队列研究数据进行分析, 并利用体外和小鼠模型进行功能研究。 结果:与谷氨酸水平相对较低组(T1)相比, 高谷氨酸水平组(T2, T3)8年后糖尿病发病风险显著增加。谷氨酸对糖尿病发病影响的体外研究显示, 谷氨酸通过增加人肝细胞SK-Hep-1中葡萄糖相关蛋白78 (GRP78)和磷酸烯醇式丙酮酸羧激酶(PEPCK)的表达诱导胰岛素抵抗。此外, 三个不同的基因FRMB4B, PLG和PARD3, 通过全基因组关联研究被鉴定出与谷氨酸显著相关。在与谷氨酸相关的基因中, 纤溶酶原(PLG)水平在几种诱导胰岛素抵抗的环境中显著升高, 并且调节谷氨酸。谷氨酸诱导的肝细胞PLG增加是由代谢型谷氨酸受体5激活引起的, 细胞外分泌后PLG水平也上调。此外,谷氨酸还增加纤溶酶原激活物抑制剂-1 (PAI-1)的表达。因此, 细胞外分泌的PLG不能被升高的PAI-1转化为纤溶酶。.
Methods
An analysis of Korean community-based Ansan-Ansung cohort study data as well as functional research using in vitro and mouse models were performed.
Results
Groups with high plasma glutamate levels (T2, T3) had a significantly increased risk of diabetes incidence after 8 years, compared to the group with relatively low glutamate levels (T1). Analysis of the effect of glutamate on diabetes onset in vitro showed that glutamate induces insulin resistance by increasing glucose-related protein 78 (GRP78) and phosphoenolpyruvate carboxykinase (PEPCK) expression in SK-Hep-1 human liver cells. In addition, three different genes, FRMB4B, PLG, and PARD3, were significantly associated with glutamate and were identified via genome-wide association studies. Among glutamate-related genes, plasminogen (PLG) levels were most significantly increased in several environments in which insulin resistance was induced, and was also upregulated by glutamate. Glutamate-induced increase in PLG in liver cells was caused by metabotropic glutamate receptor 5 activation, and PLG levels were also upregulated after extracellular secretion. Moreover, glutamate increased the expression of plasminogen activator inhibitor-1 (PAI-1). Thus, extracellular secreted PLG cannot be converted to plasmin (fibrinolytic enzyme) by increased PAI-1. Conclusions: Increased glutamate is closely associated with the development of diabetes, and it may cause metabolic disorders by inhibiting the fibrinolytic system, which plays an important role in determining blood clots, a hallmark of diabetes. 背景:谷氨酸是一种主要的神经递质, 尽管它在非神经元器官中引起细胞毒性和炎症。本研究旨在探讨与2型糖尿病发病相关的谷氨酸在肝脏中诱导的代谢紊乱。 方法:对韩国基于社区的Ansan-Ansung队列研究数据进行分析, 并利用体外和小鼠模型进行功能研究。 结果:与谷氨酸水平相对较低组(T1)相比, 高谷氨酸水平组(T2, T3)8年后糖尿病发病风险显著增加。谷氨酸对糖尿病发病影响的体外研究显示, 谷氨酸通过增加人肝细胞SK-Hep-1中葡萄糖相关蛋白78 (GRP78)和磷酸烯醇式丙酮酸羧激酶(PEPCK)的表达诱导胰岛素抵抗。此外, 三个不同的基因FRMB4B, PLG和PARD3, 通过全基因组关联研究被鉴定出与谷氨酸显著相关。在与谷氨酸相关的基因中, 纤溶酶原(PLG)水平在几种诱导胰岛素抵抗的环境中显著升高, 并且调节谷氨酸。谷氨酸诱导的肝细胞PLG增加是由代谢型谷氨酸受体5激活引起的, 细胞外分泌后PLG水平也上调。此外,谷氨酸还增加纤溶酶原激活物抑制剂-1 (PAI-1)的表达。因此, 细胞外分泌的PLG不能被升高的PAI-1转化为纤溶酶。.