Contribution of excitatory amino acids to hypoglycemic counter-regulation

We determined the contribution of central N-methyl-D-aspartate (NMDA) recep tor activation to the neuro-endocrine counter-regulatory response to insuli n-induced hypoglycemia. Glucose kinetics, gluconeogenic substrate balance a nd counter-regulatory hormonal responses were determined in two groups of c onscious dogs fitted with chronic vascular catheters and intracerebroventri cular (i.c.v.) cannula. Peripheral insulin infusion (5 mU/kg per min for 3 h) decreased plasma glucose levels 40% and increased the rate of glucose ap pearance (R-a) 2-fold. This was associated with significant increases in ne t hepatic uptake of glycerol and lactate, without any change in the net hep atic uptake of alanine. i.c.v. pretreatment with MK-801. an NMDA receptor a ntagonist, blunted (50%) the rise in glucose R-a as well as the increase in the net hepatic uptake of glycerol and lactate. Hypoglycemia increased pla sma cortisol (3-fold to 14.3+/-1 mg/dl) and epinephrine levels (14-fold to 3811+/-172 pg/ml), and this stress response was attenuated (30% and 60%, re spectively) by MK-801 pretreatment. In controls, MK-801 did not alter the i ncrease in norepinephrine or glucagon elicited by hypoglycemia. These resul ts indicate that during hypoglycemia, central excitatory amino acids contri bute to the modulation of the glucoregulatory response through activation o f NMDA receptors, resulting in stimulation of the sympathoadrenal and hypot halamic-pituitary adrenal axis. This mechanism appears to play an important role in the sustained elevation in hepatic glucose production during hypog lycemia. (C) 2001 Elsevier Science B.V. All rights reserved.