BACKGROUND: Elevated levels of glutamate in brain fluids, in the context of several neurodegenerative conditions, are associated with a worsened neurological outcome. Because there is a clear relationship between brain glutamate levels and glutamate levels in the blood, and an association of the latter with stress, the purpose of this study was to investigate the effects of glucose, insulin, and glucagon on rat blood glutamate levels. METHODS: Rats received either 1 mL/100 g of rat body weight (BW) intravenous isotonic saline (control), 150 mg/1 mL/100 g BW intravenous glucose, 75 mg/1 mL/100 g BW intravenous glutamate, 50 g/100 g BW intraparitoneal glucagon, or 0.2 UI/100 g BW intraparitoneal insulin. Blood samples were subsequently drawn at 0, 30, 60, 90, and 120 minutes for determination of blood glutamate and glucose levels. RESULTS: We observed a significant decrease in blood glutamate levels at 30 minutes after injection of glucose (P<0.05), at 30 and 60 minutes after injection of insulin (P<0.05), and at 90 and 120 minutes after injection of glucagon. Plasma glucose levels were elevated after infusion of glutamate and glucose but were decreased after injection of insulin. CONCLUSIONS: The results of this study demonstrate that glucose, insulin, and glucagon significantly reduce blood glutamate levels. The effect of insulin is immediate and transient, whereas the effect of glucagon is delayed but longer lasting, suggesting that the sensitivity of pancreatic glucagon and insulin-secreting cells to glutamate is dependent on glucose concentration. The results of this study provide insight into blood glutamate homeostasis and may assist in the implementation of new therapies for brain neuroprotection from excess glutamate.