Division of Endocrine and Kidney Disease Research, Department of Chronic Disease Convergence Research, Korea National Institute of Health, Korea Disease Control and Prevention Agency, Cheongju-si, Chungcheongbuk-do, Korea.
J Diabetes. 2023 Sep;15(9):777-786. doi: 10.1111/1753-0407.13429. Epub 2023 Jun 14.
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.
An analysis of Korean community-based Ansan-Ansung cohort study data as well as functional research using in vitro and mouse models were performed.
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.
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.
谷氨酸是一种主要的神经递质，但它会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引起的代谢紊乱。
对韩国社区安山-安城队列研究数据进行分析，并通过体外和小鼠模型进行功能研究。
与谷氨酸水平相对较低的组（T1）相比，血浆谷氨酸水平较高（T2、T3）的组在 8 年后发生糖尿病的风险显著增加。体外分析谷氨酸对糖尿病发病的影响表明，谷氨酸通过增加葡萄糖相关蛋白 78（GRP78）和磷酸烯醇丙酮酸羧激酶（PEPCK）在 SK-Hep-1 人肝细胞中的表达来诱导胰岛素抵抗。此外，通过全基因组关联研究鉴定了与谷氨酸显著相关的三个不同基因 FRMB4B、PLG 和 PARD3。在与谷氨酸相关的基因中，纤溶酶原（PLG）水平在多种诱导胰岛素抵抗的环境中增加最显著，并且也被谷氨酸上调。谷氨酸诱导肝细胞中 PLG 增加是由代谢型谷氨酸受体 5 激活引起的，细胞外分泌也会导致 PLG 上调。此外，谷氨酸增加了纤溶酶原激活物抑制剂-1（PAI-1）的表达。因此，由于增加的 PAI-1，细胞外分泌的 PLG 不能转化为纤溶酶（纤维蛋白溶解酶）。
谷氨酸水平升高与糖尿病的发生密切相关，它可能通过抑制纤溶系统导致代谢紊乱，纤溶系统在决定血栓形成方面起着重要作用，而血栓形成是糖尿病的一个标志。
