Central NMDA enhances hepatic glucose output and non-insulin-mediated glucose uptake by a nonadrenergic mechanism.
One of the hallmarks of the stress response is an increased rate of hepatic glucose production (HGP) which, in conjunction with the presence of insulin resistance, leads to hyperglycemia. Excitatory amino acids (EAA) within the brain mediate some of the cardiovascular responses to stress, but their role in the hormonal and metabolic alterations is poorly defined. The aim of the present study was to determine whether the intracerebroventricular (i.c.v.) injection of either N-methyl-D-aspartate (NMDA) or kainate would produce metabolic alterations comparable to those observed under stress conditions. An i.c.v. cannula and vascular catheters were placed in rats prior to the experiment. After an overnight fast, HGP and peripheral glucose utilization (GU) were assessed in conscious unrestrained rats using [3-3H]glucose. Arterial glucose levels were increased 34% by 15 min after the i.c.v. injection of NMDA (1 microgram) and remained elevated throughout the 3-h protocol. The hyperglycemia resulted from an early increase in HGP (84%) that exceeded a smaller elevation (66%) in GU. The increased glucose flux was associated with sustained insulinopenia (-30%), and elevated levels of corticosterone (40-100%) and epinephrine (75-216%). The hormonal and glucose metabolic responses were quantitatively similar, although of shorter duration, in rats injected with kainate (10 ng). Intravenous adrenergic blockade completely prevented the NMDA-induced hyperglycemia. Adrenergic blockade blunted the early rise in HGP, so that in this group the NMDA-induced increase in HGP was offset by a comparable elevation in GU.(ABSTRACT TRUNCATED AT 250 WORDS)
Molina
P E
PE
Department of Surgery, State University of New York at Stony Brook 11794-8191.
Tepper
P G
PG
Yousef
K A
KA
Abumrad
N N
NN
Lang
C H
CH
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D006339:Heart Rate / Q000187:drug effects; D006728:Hormones / Q000097:blood*; D007276:Injections, Intraventricular; D007328:Insulin; D007608:Kainic Acid / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D016202:N-Methylaspartate / Q000008:administration & dosage*; D009638:Norepinephrine / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000097:blood / Q000378:metabolism*
D006728:Hormones; D007328:Insulin; D016202:N-Methylaspartate; D005947:Glucose; D007608:Kainic Acid; D009638:Norepinephrine