Thiamin deficiency impairs endotoxin-induced increases in hepatic glucose output.

We addressed the role of thiamin, a cofactor for several enzymes involved in glucose metabolism, in the glucose metabolic response to endotoxin. Characterized by hyperglycemia, increased hepatic glucose production exceeding elevated rates of whole-body glucose utilization, this response is mediated by hormones and cytokines and is dependent on the immune and nutritional status of the host. We hypothesized that a thiamin-deficient state would impair the metabolic response to endotoxin. Rats were fed a thiamin-deficient or control diet for 6 wk before in vivo assessment of glucose kinetics. In control rats, Escherichia coli endotoxin increased the rate of glucose appearance (+76%), disappearance (+70%), and metabolic clearance (+50%). Thiamin deficiency resulted in increased plasma glucose (18%) and lactate (3- to 4-fold) as well as in a 30% decrease in insulin and an increase in glucagon (2.6-fold) and corticosterone (3.6-fold). Thiamin deficiency inhibited the endotoxin-induced hyperglycemia and the rise in hepatic glucose production, glucose utilization, and metabolic clearance rate.

Modulation of endotoxin-induced changes in hemodynamics and glucose metabolism by an N-methyl-D-aspartate receptor antagonist.

Excitatory amino acids (EAAs) are the principal mediators of fast excitatory neurotransmission in the mammalian central nervous system. Previous studies have demonstrated that N-methyl-D-aspartate (NMDA), an EAA agonist, produces a stress response that mimics that observed in animals receiving lipopolysaccharide (LPS). The present investigation determined the role that NMDA receptors play in the hemodynamic, metabolic, and hormonal changes induced by LPS. Chronically catheterized fasted rats received LPS with or without prior injection of MK 801, an NMDA receptor antagonist. LPS produced a classical stress response characterized by hypotension, tachycardia, increased glucose flux, and elevated plasma levels of glucagon, corticosterone, and catecholamines. MK 801 (intravenously) prevented the tachycardia in response to LPS, but did not consistently alter the fall in arterial blood pressure. The NMDA receptor antagonist also blunted the early elevation in plasma epinephrine and norepinephrine levels seen in LPS-injected rats, and this was associated with a smaller increment in plasma glucose and lactate concentrations and glucose flux. To confirm that MK 801 was functioning by antagonizing NMDA receptors within the brain, a second group of rats received an intracerebroventricular injection of MK 801 prior to LPS. The central administration of MK 801 also attenuated the increase in heart rate. These results indicate that central NMDA receptor stimulation mediates the LPS-induced tachycardia and suggest that the partial inhibition of the glucose metabolic response to LPS by MK 801 resulted from the smaller increment in plasma catecholamines.

Differential control of glucoregulatory hormone response and glucose metabolism by NMDA and kainate.

The aim of the present study was to elucidate the effect of kainate and N-methyl-D-aspartate (NMDA), two different excitatory amino acid (EAA) agonists, on glucoregulatory hormone production and whole body glucose metabolism. Rates of hepatic glucose production (HGP) and peripheral glucose utilization (GU) were assessed in overnight fasted, catheterized, conscious rats using [3-3H]glucose. At the highest dose of kainate examined (16 mg/kg), glucose levels increased 97% after 1 h; thereafter, glucose fell towards basal values but was still elevated 25% at the end of the 3 h experiment. This hyperglycemia resulted from a rapid increase in HGP that exceeded an increased rate of GU. Both HGP and GU were elevated 86% throughout the final 2 h of the experiment. NMDA induced changes in glucose flux that were qualitatively similar, yet of smaller magnitude and of shorter duration, than those produced by kainate. Kainate-induced increases in glucose metabolism were associated with an early transient hyperinsulinemia followed by a period of insulinopenia, and sustained increases in the plasma concentrations of glucagon, corticosterone, epinephrine and norepinephrine. In contrast, sustained increases in glucagon and catecholamines, as well as the late hypoinsulinemia were not detected in NMDA-treated rats. Adrenergic blockade attenuated the kainate- but not the NMDA-induced increase in glucose metabolism. These results indicate that EAA agonists that bind preferentially to different receptor subtypes produce qualitatively similar changes in glucose metabolism. Whereas the increased HGP in kainate-injected rats was associated with sustained elevations in glucagon, catecholamines and corticosterone, NMDA only transiently elevated circulating glucocorticoid levels, suggesting a different mechanism of action. These data, support the involvement of EAA in various aspects of glucoregulation.

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)

Role of IL-1 alpha in central nervous system immunomodulation of glucoregulation.

Hyperglycemia is a hallmark of the stress response, and has been largely attributed to elevated plasma levels of catabolic hormones. Recently, various cytokines have been shown to be endogenously produced within the brain and may represent an important component of the central regulation of this metabolic response. Therefore, the aim of the present study was to determine whether the intracerebroventricular (i.c.v.) injection of one such peptide, interleukin (IL)-1, can produce hormonal and 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. Whole body glucose flux was assessed in overnight fasted conscious unrestrained rats using [3-3H]glucose. A mild hyperglycemia was elicited 20 min after the i.c.v. injection of IL-1 alpha (human recombinant, 100 ng) that was not detected in control rats. Glucose levels gradually increased and were 26% higher than control values during the last hour of the 3 h experimental period. The hyperglycemia resulted from a 44% increase in the rate of hepatic glucose output (HGO), which preceded a proportional rise in peripheral glucose utilization. No increase in metabolic clearance rate was observed, suggesting that the increased glucose uptake was the result of mass action. The increased glucose flux was associated with a transient hyperinsulinemia (+95%), and sustained elevations in the arterial concentrations of glucagon (56%) and corticosterone (175%). In contrast, glucose flux was not altered by intravenous administration of the same dose of IL-1 alpha, or i.c.v. injection of IL-1 beta, or heat-inactivated IL-1 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

[18F]haloperidol binding in baboon brain in vivo.

The binding of [18F]haloperidol to dopamine D2 and to sigma recognition sites in baboon brain was examined using positron emission tomography (PET). Studies were performed at baseline and after treatment with either haloperidol (to evaluate saturability), (+)-butaclamol (which has specificity for dopamine D2 receptors) or (-)-butaclamol (which has specificity for sigma sites). Binding was widespread. Treatment with (-)-butaclamol had no effect, whereas (+)-butaclamol selectively reduced the uptake in striatum. Haloperidol increased the clearance rate from all brain regions. These results indicate that the binding profile of [18F]haloperidol does not permit the selective examination of either dopamine D2 or sigma sites using PET.

Nutritional and metabolic characterization of a thiamine-deficient rat model.

The effects of a thiamine-deficient diet on plasma and tissue vitamin concentrations and on whole-body glucose metabolism were assessed. Male Sprague-Dawley rats (175 to 200 g body weight) fed a thiamine-deficient (TD) or nutritionally complete purified diet were used for plasma thiamine mononitrate and monophosphate and for red blood cell and tissue thiamine pyrophosphate (TPP) determinations weekly for up to 5 weeks. Additional rats were used for assessment of basal glucose kinetics by using a primed constant infusion of [3-3H]glucose. Plasma thiamine mononitrate levels decreased 60% at 1 week and were undetectable after 5 weeks on the diet. Plasma thiamine monophosphate decreased 80% after 1 week on the TD diet, and levels were undetectable after 4 weeks on the diet. Red blood cell TPP in the TD group decreased progressively with time: 54% at 1 week, 86% at 3 weeks, and 92% at 5 weeks. At 1 and 4 weeks, the decrease in tissue TPP was significant in the liver (65% and 89%, respectively), gut (52% and 94%, respectively), spleen (40% and 60%, respectively), and skeletal muscle (37% and 76%, respectively), with the brain (7% and 84%, respectively) showing the slowest initial rate of depletion. The TD diet did not alter plasma glucose concentrations, but it increased plasma lactate by 75% and plasma pyruvate by 50% to 75%. Rates of hepatic glucose production and peripheral glucose utilization were not different between the control and TD rats at 2 weeks, but they were 25% higher in the TD rats after 6 weeks on the diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Haloperidol blocks the uptake of [18F]N-methylspiroperidol by extrastriatal dopamine receptors in schizophrenic patients.

We had previously demonstrated extrastriatal uptake of [18F]N-methylspiroperidol (18F-NMS) in the human brain. This study evaluates the effect of haloperidol on 18F-NMS binding in extrastriatal brain regions. Six schizophrenic patients on haloperidol underwent two PET scans with 18F-NMS at 12 h and at 6 days after haloperidol withdrawal. There was a significant increase in 18F-NMS uptake in striatal, thalamic, and temporal regions but not in frontal, occipital, or cerebellar regions, following drug withdrawal. Haloperidol's ability to block the uptake of 18F-NMS is an indication of the specificity of the radioligand's binding in these regions and supports the postmortem data demonstrating the presence of dopamine D2 receptors in the thalamus and temporal cortex of the human brain.