Research reportThe effects of pharmacological doses of 2-deoxyglucose on cerebral blood flow in healthy volunteers
Introduction
Cerebral glucose deprivation provides a useful experimental paradigm for the investigation of cerebral blood flow (CBF) in both preclinical and clinical studies. Glucose is the primary energy source for the central nervous system, and glucose deprivation, therefore, influences neuronal functioning throughout the brain. Inhibition of cerebral glucose utilization due to moderate or severe hypoglycemia 8, 18 or blockade of glucose metabolism with pharmacological doses of 2-deoxyglucose (2DG) 6, 18 results in significant increases in CBF in rodents. In humans, the CBF response to insulin-induced hypoglycemia is less robust and consistent, with both increases 11, 23, 31, 37 and little or no change 3, 12, 24, 32 reported. The reasons for these conflicting results are unclear and may be related to degree of hypoglycemia, alterations in cerebral metabolic rate or to the methods employed in the determination of CBF.
Previous data on the cerebral effects of acute glucoprivation in man pertain only to insulin-induced hypoglycemia. Administration of pharmacological doses of 2DG is an alternative paradigm for the assessment of glucoprivic effects on CBF. 2DG is a glucose analog that is transported across the blood-brain barrier into brain tissue where it is phosphorylated to 2-deoxyglucose-6-phosphate (2DG6P) but is not metabolized further down the glycolytic pathway. The 2DG6P then accumulates to levels that inhibit glucose-6-phosphate isomerase and thus blocks glycolysis and oxidative metabolism of glucose [20]. Following the infusion of loading doses of 2DG, blood glucose levels are elevated, presumably mainly due to sympathetic activation, glycogenolysis, reduced body metabolism of glucose, and gluconeogenesis [2]. Thus in contrast to insulin-induced hypoglycemia, 2DG directly inhibits glycolytic flux in the brain while simultaneously producing hyperglycemia [28].
We have previously investigated the effects of pharmacological doses of 2DG on blood flow in 29 brain regions in the conscious unrestrained adult rat and found increases in most regions. The largest increases were observed in the frontal, superior temporal and sensorimotor cortices, cingulate gyrus, basal ganglia, thalamus, limbic regions and the genu of the corpus callosum [6]. Because of the lack of data regarding the effects of 2DG on CBF in humans and its relatively unique mechanism of glucoprivation, we have investigated the influence of this agent on CBF in healthy human subjects by means of positron emission tomography (PET). Because of our previous study in rats 6, 27, we anticipated that 2DG-induced glucoprivation would also increase rCBF in humans and used a region-of-interest (ROI) approach to describe which of the brain areas would be particularly affected. We also examined the 2DG effects on physiologic (temperature, blood pressure, heart rate) and behavioral (self rating of hunger, drowsiness, tension) measures. Finally, as body temperature 16, 33 and blood pressure [40] may be regulated by the hypothalamus, the relationship of 2DG-induced changes in these physiologic variables to hypothalamic rCBF were examined.
Section snippets
Subjects
Thirteen healthy subjects (mean age±S.D.: 31.8±6.2 years; 11 males, 2 females) were recruited through the volunteer pool of the National Institutes of Health (NIH) and participated in the study after giving written informed consent to a protocol approved by an Institutional Review Board. The subjects were in good physical health, as evidenced by physical exam, SMAC, thyroid function test, CBC, urinalysis, HIV antibody test, toxicology screen and ECG. The subjects had no past or current
2DG-induced changes in CBF
2DG administration increased rCBF in the most of the areas that were examined, (Table 1). The increases were statistically significant in the cingulate gyrus (p=0.04), sensorimotor cortex (p=0.04), superior temporal cortex (p=0.03), occipital cortex (p=0.02), basal ganglia (p=0.03), limbic system (p=0.04) and hypothalamus (p<0.01). In the whole brain (p=0.07) and the frontal cortex (p=0.08), 2DG produced marginal effects while no significant effects were observed in the corpus callosum (p=0.58)
Discussion
This is to our knowledge the first report on the influence of 2DG-induced glucoprivation on CBF in human subjects. Bolus administration of pharmacological doses of 2DG (40 mg/kg) resulted in a robust activation of rCBF in cortical and subcortical areas including the cingulate gyrus, sensorimotor cortex, superior temporal cortex, occipital cortex, basal ganglia, limbic system and hypothalamus (mean percent change from baseline 20.5–42). The largest increase in rCBF increase occurred in the
Acknowledgements
The authors gratefully acknowledge contributions of Christopher Bir, Ian Kronish, Thomas Herman, Sara Krause and the nursing staff of 4 East Clinical Care Unit, National Institutes of Health. This study was supported by a grant from the National Association for Research in Schizophrenia and Affective Disorders (NARSAD).
References (40)
- et al.
Adrenal demedullation blocks and brain norepinephrine depletion potentiates the hyperglycemic response to a variety of stressors
Brain Res.
(1989) Experimental approaches to human stress research: assessment of neurobiological mechanisms of stress in volunteers and psychiatric patients
Biol. Psychiatry
(1989)- et al.
The effects of pharmacologic doses of 2-deoxy-d-glucose on local cerebral blood flow in the awake, unrestrained rat
Brain Res.
(1993) - et al.
Effects of acute metabolic stress on plasma progesterone and testosterone in male subjects: relationship to pituitary-adrenocortical axis activation
Life Sci.
(1997) - et al.
Regional cerebral blood flow in normal man during insulin-induced hypoglycemia and in the recovery period following glucose infusion
Metabolism
(1992) - et al.
Modulation of cognition-specific cortical activity by gonadal steroids: a positron-emission tomography study in women
Proc. Natl. Acad. Sci. U.S.A.
(1997) - et al.
Adaptation in brain glucose uptake following recurrent hypoglycemia
Proc. Natl. Acad. Sci. U.S.A.
(1994) - et al.
Alprazolam attenuates metabolic stress-induced neuroendocrine and behavioral effects in humans
Psychopharmacology (Berl.)
(1991) - et al.
Effects of metabolic perturbation on plasma homovanillic acid in schizophrenia. Relationship to prefrontal cortex volume
Arch. Gen. Psychiatry
(1993) - et al.
Cerebral blood flow, plasma catecholamines, and electroencephalogram during hypoglycemia and recovery after glucose infusion
J. Neurosurg. Anesthesiol.
(1994)
Global cerebral blood flow decreases during pain
J. Cereb. Blood Flow. Metab.
Factors affecting dispersion correction for continuous blood withdrawal and counting systems
J. Nucl. Med.
Cerebral blood flow and metabolism in therapeutic insulin coma
Metabolism
The cerebral metabolic effects of acutely induced hypoglycemia in human subjects
Metabolism
Effect of acute metabolic stress on pituitary-adrenal axis activation in patients with schizophrenia
Am. J. Psychiatry
Plasma levels of catecholamines and corticotrophin during acute glucopenia induced by 2-deoxy-d-glucose in normal man
Clin. Auton. Res.
Posterior hypothalamus and the regulation of body temperature
Fed. Proc.
Effects of elevated plasma epinephrine on glucose utilization and blood flow in conscious rat brain
Am. J. Physiol.
Examination of potential mechanisms in the enhancement of cerebral blood flow by hypoglycemia and pharmacological doses of deoxyglucose
J. Cereb. Blood Flow. Metab.
Blockade of cerebral blood flow response to insulin-induced hypoglycemia by caffeine and glibenclamide in conscious rats
J. Cereb. Blood Flow. Metab.
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