Impacts of glutamate, an exercise-responsive metabolite on insulin signaling

Disruption of the insulin signaling pathway leads to insulin resistance (IR). IR is characterized by impaired glucose and lipid metabolism. Elevated levels of circulating glutamate are correlated with metabolic indicators and may potentially predict the onset of metabolic diseases. Glutamate receptor antagonists have significantly enhanced insulin sensitivity, and improved glucose and lipid metabolism. Exercise is a well-known strategy to combat IR. The aims of our narrative review are to summarize preclinical and clinical findings to show the correlations between circulating glutamate levels, IR and metabolic diseases, discuss the causal role of excessive glutamate in IR and metabolic disturbance, and present an overview of the exercise-induced alteration in circulating glutamate levels. A literature search was conducted to identify studies on glutamate, insulin signaling, and exercise in the PubMed database. The search covered articles published from December 1955 to January 2024, using the search terms of “glutamate”, “glutamic acid”, “insulin signaling”, “insulin resistance”, “insulin sensitivity”, “exercise”, and “physical activity”. Elevated levels of circulating glutamate are correlated with IR. Excessive glutamate can potentially hinder the insulin signaling pathway through various mechanisms, including the activation of ectopic lipid accumulation, inflammation, and endoplasmic reticulum stress. Glutamate can also modify mitochondrial function through Ca2+ and induce purine degradation mediated by AMP deaminase 2. Exercise has the potential to decrease circulating levels of glutamate, which can be attributed to accelerated glutamate catabolism and enhanced glutamate uptake. Glutamate may act as a mediator in the exercise-induced improvement of insulin sensitivity.