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.
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。.
Keywords: 2型糖尿病; Korean Genome and Epidemiology Study; glutamate; metabotropic glutamate receptor 5; plasminogen; plasminogen activator inhibitor-1; type 2 diabetes; 代谢性谷氨酸受体5; 纤溶酶原; 纤溶酶原激活物抑制剂-1; 谷氨酸; 韩国基因组和流行病学研究.
© 2023 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.