Increased glutamate in type 2 diabetes in the Korean population is associated with increased plasminogen levels

• Published in: Journal of diabetes Vol. 15; no. 9; pp. 777 - 786
• Main Authors: Lee, Hyo Jung, Yeom, Jeong Won, Yun, Ji Ho, Jang, Han Byul, Yoo, Min-Gyu, Kim, Hyo-Jin, Koo, Soo Kyung, Lee, Hye-Ja
• Format: Journal Article
• Language: English
• Published: Australia John Wiley & Sons, Inc 01.09.2023; Wiley Publishing Asia Pty Ltd
• Subjects: Diabetes; Insulin resistance; Metabolic disorders; Original; plasminogen; plasminogen activator inhibitor-1; type 2 diabetes; metabotropic glutamate receptor 5; Korean Genome and Epidemiology Study; glutamate
• ISSN: 1753-0393; 1753-0407
• DOI: 10.1111/1753-0407.13429

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.