Glutamate is a major excitatory neurotransmitter and is involved in the ER stress and β-cell dysfunction, which are important clinical features of diabetes mellitus. However, metabolic studies of diabetes in relation to glutamate are not well understood. In this regard, we tried to search for the function of glutamate in type 2 diabetes. We found that glutamate levels were significantly increased in both prediabetic and diabetic participants in 10 years follow-up study (Korean Genome and Epidemiology Study: Ansan-Ansung cohort). And also, we observed that glutamate is associated with FERM domain-containing protein 4B (FRMD4B), plasminogen (PLG) and partitioning-defective 3 (PARD3) by genome-wide association studies (GWAS). Among them, PLG levels were not only significantly increased by palmitate treatment, which is general model for induction of insulin resistance, but also increased by glutamate treatment. To demonstrate the association between PLG and type 2 diabetes, we treated thapsigargin (ER stress) or oligomysin (mitochondrial dysfunction) in Sk-Hep I cells, and observed that PLG levels were significantly increased in these conditions. Consistently, PLG overexpression increased expression of ER stress-related factors; however, repression of PLG expression by plg siRNA attenuated these changes. Our results demonstrate that high levels of glutamate are associated with development of diabetes, and are assumedly regulated by PLG.
H. Lee: None. J. Yun: None. H. Kim: None. H. Jang: None. S. Park: None. H. Lee: None.
Korea National Institute of Health (2017-NG64001-02)