Central NMDA enhances hepatic glucose output and non-insulin-mediated glucose uptake by a nonadrenergic mechanism

Abstract

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 μg) 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. These data indicate that NMDA and kainate, two EAA that bind to different receptor subtypes, act centrally to increase circulating levels of stress hormones and enhance glucose flux. EAA increase HGP and noninsulin-mediated GU by peripheral tissues, with the later response being influenced by both the mass action effect of hyperglycemia as well as an increased avidity of tissues for glucose. These data support the involvement of EAA in the central control of glucoregulation following brain injury.