Administration Of 2DG Research Articles

Effects of acute metabolic stress on striatal dopamine release in healthy volunteers

Several lines of evidence indicate that a variety of metabolic stressors, including acute glucose deprivation are associated with dopamine release. Pharmacologic doses of the glucose analogue, 2-deoxyglucose (2DG) cause acute glucoprivation and are associated with enhanced dopamine turnover in preclinical studies. In this study, we utilized [11C]raclopride PET to examine 2DG-induced striatal dopamine release in healthy volunteers. Six healthy volunteers underwent PET scans involving assessment of 2DG-induced (40 mg/kg) decrements in striatal binding of the D(2)/D(3) receptor radioligand [11C]raclopride. Decreases in [11C]raclopride specific binding reflect 2DG-induced changes in synaptic dopamine. Specific binding significantly decreased following 2DG administration, reflecting enhanced synaptic dopamine concentrations (p =.02). The administration of 2DG is associated with significant striatal dopamine release in healthy volunteers. Implications of these data for investigations of the role of stress in psychiatric disorders are discussed.

Evaluation of 2-deoxy-D-glucose for induction of a stress response in pigs

Abstract Objective To determine the most effective route and dose for 2-deoxy-D-glucose (2DG) administration in swine, kinetics of 2DG, endogenous glucose concentration in the blood, effects of 2DG on Cortisol concentration, and effects of 2DG administration in vivo on lymphocyte proliferation in vitro. Animals 14 Salmonella-free male and female mixed-breed pigs. Procedure A cannula was inserted in the femoral artery of each pig to allow for frequent blood collection with minimal external stress. The concentration and duration of 2DG in the blood was monitored while varying dose (250, 500, or 750 mg/kg of body weight) and route (IV, SC, IM, or IP) of 2DG administration. Blood samples were collected at various time points and assayed for lymphocyte response to concanavalin A and Cortisol, endogenous glucose, and 2DG concentrations. Results The 2 best routes for administration of 2DG were IV and SC. If the IV route was chosen, the optimal dose was 500 mg of 2DG/kg; the optimal dose for SC administration was 750 mg/kg. Conclusions 2DG induces a stress response in pigs similar to that in rodents. The use of 2DG in a porcine stress model should be effective for studying the possible role of stress in the pathogenesis and shedding of microorganisms. (Am J Vet Res 1999;60:708–713)

Dorsomedial hindbrain participation in glucoprivic feeding response to 2DG but not 2DG-induced hyperglycemia or activation of the HPA axis

2-Deoxy- d-glucose (2DG) is a glucose analogue that inhibits intracellular utilization of glucose and produces a characteristic behavioral response known as glucoprivic feeding. The area postrema (AP) is a caudal hindbrain structure shown previously to be involved in 2DG-induced glucoprivic feeding. In addition, peripheral administration of 2DG is known to elicit activation of both the hypothalamic-pituitary-adrenal (HPA) axis and the sympathoadrenomedullary system. The neural substrates for these neuroendocrine and neural responses to 2DG are not known although they may also involve the AP. The possible role of the AP in 2DG-induced feeding, activation of the HPA axis and hyperglycemia was investigated in Sprague–Dawley rats with lesions centered on the area postrema (APX) and sham-operated (SHM) rats administered 2DG (200 mg/kg) or physiological saline (1 ml/kg). Peripheral administration of 2DG evoked a feeding response in SHM rats that was abolished in APX animals. Interestingly, 2DG administered at this dose produced a significant increase in plasma corticosterone and plasma glucose in both SHM and APX rats for up to 4 h after drug treatment. Collectively, these findings suggest that the AP is involved in the behavioral (feeding) response to peripheral administration of 2DG, but does not appear to be a common neural substrate for the neuroendocrine (HPA axis) and sympathoadrenal (hyperglycemic) responses to this agent.

Metabolic interfaces between growth and reproduction. V. Pulsatile luteinizing hormone secretion is dependent on glucose availability.

To test the hypothesis that mechanisms controlling the secretion of LH are modulated by glucose availability, the acute effects of glucoprivation were studied. The model was the gonadectomized male lamb raised on a limited diet of artificial milk. The approach was to monitor LH secretion before and after the administration of a competitive antagonist of glucose metabolism, 2-deoxyglucose (2DG). We first determined whether LH secretion was influenced by glucose availability by administering 2DG at several doses. Peripheral administration of the glucose antagonist (240 and 480 mg/kg 2DG, single iv injection) transiently decreased LH pulse frequency, but not LH pulse amplitude. By contrast, LH secretion (frequency or amplitude) was not affected by lower doses (60 or 120 mg/kg) of the glucose antagonist. A second study was conducted to determine whether either the pituitary gland or the GnRH neurosecretory system per se is directly affected by short term glucoprivation. The competency of the pituitary was assessed by administering GnRH during the time when LH secretion is suppressed by pharmacological glucose blockade. Similarly, the function of the GnRH neurosecretory system was assessed by administering a GnRH secretagogue (N-methyl-D,L-aspartate) under the same glucoprivic conditions. In response to an optimized iv dose of 2DG, LH pulse frequency decreased. However, in lambs that received either GnRH or N-methyl-D,L-aspartate during the period of glucoprivation, LH pulse frequency was sustained at levels comparable to those before 2DG was given. To determine whether the effect of glucoprivation was central in origin, the glucose antagonist was administered into the lateral cerebral ventricle at 1/100th the doses used peripherally. Central administration of 2DG, independent of dose, transiently decreased LH pulse frequency, but not pulse amplitude. However, unlike the case with peripheral injection, plasma glucose values did not change after the administration of any dose of 2DG tested centrally. These findings indicate that glucose availability in the developing sheep influences LH secretion. Moreover, based upon analysis of LH pulse frequency, glucoprivation does not directly impair either the pituitary gland or the GnRH neurosecretory system. Collectively, these results suggest that glucose availability affects LH secretion by acting within the central nervous system at a detection site(s) peripheral to the GnRH neuron.

Effect of acute glucose antagonism on hypophyseal hormones and concentrations of insulin-like growth factor (IGF)-I and IGF-binding proteins in serum, anterior pituitary, and hypothalamus of ewes.

The objectives of this study were to determine whether 2-deoxy-D-glucose (2DG), a metabolic inhibitor of glucose, 1) differentially affected release of LH, growth hormone (GH) and prolactin (PRL); 2) decreased anterior pituitary response to GnRH; and 3) altered concentrations of insulin-like growth factor I (IGF-I) and intensity of 125I-IGF-I binding to proteins (IGFBPs) in serum, anterior pituitary (AP), and hypothalamus (preoptic are [POA], medial basal hypothalamus [MBH], and stalk median eminence [SME]). In trial 1, mature, ovariectomized, crossbred ewes were treated with a single s.c. injection of either saline (n = 5) or 2DG (n = 5; 0.1 g/kg BW). Administration of 2DG suppressed (p < 0.05) concentrations of LH but did not affect (p > 0.05) serum concentrations of GH or PRL. In trial 2, ovariectomized ewes received injections of saline or 2DG, and each group was subdivided to receive either saline or GnRH analog (5 micrograms; Des-Gly10-[D-Ala6]) 2 h later. Administration of 2DG suppressed (p < 0.05) serum concentrations of LH before administration of GnRH; however, release of LH in response to exogenous GnRH was greater (p < 0.05) in ewes that received 2DG. Treatment with 2DG did not affect (p > 0.05) concentrations of FSH before or after administration of GnRH. In trial 3, 10 ovariectomized ewes were slaughtered 2 h after treatment with saline (n = 5) or 2DG (n = 5). Serum and tissues collected at slaughter (AP, MBH, SME, and POA) were analyzed for concentrations of IGF-I by RIA and intensity of 125I-IGF-I binding to proteins by ligand blotting.(ABSTRACT TRUNCATED AT 250 WORDS)

Cholecystokinin and cholinergic agents on periodic gallbladder contraction in dogs

1. The effect of cholecystokinin octapeptide (CCK-OP), methacholine, 2-deoxy-D-glucose (2DG) and gastric distension on gallbladder contraction in relation to interdigestive activity was studied in four conscious dogs with chronic biliary fistulae. 2. The gallbladder contraction in response to CCK-OP was inhibited by atropine and by a ganglionic blocking agent, the characteristics suggesting competitive inhibition. 3. Spontaneous contraction of the gallbladder was still observed after the administration of CCK-OP, methacholine or 2DG. With ganglionic blockade, CCK(-)-OP or methacholine initiated gallbladder contraction, but the spontaneous peak was no longer observed. 4. CCK-OP (100 ng kg-1), methacholine or 2DG advanced the spontaneous contraction of the gallbladder, but did not alter the duration of the cycle. 5. Gastric distension initiated gallbladder contraction. This was abolished by ganglionic blockade. The contraction did not continue in spite of continuous gastric distension, and the spontaneous contraction reappeared 100 min following the pre-distension control.

The effect of cellular glucoprivation on skin temperature regulation in the rat

Studies were undertaken to determine the effects of cellular glucoprivation on temperature responses in morphine-addicted and placebo-treated rats and to compare these responses to those observed during naloxone-precipitated morphine withdrawal. Naloxone caused a tail skin temperature (TST) response of 5.7 ± 0.5°C in morphine-dependent rats. Intraperitoneal administration 2-deoxyglucose (2DG) caused TST responses in placebo-treated and morphine-dependent rats of 4.8 ± 0.6 and 6.2 ± 0.5°C, respectively. These data indicate that the activation of the sympathetic nervous system by cellular glucoprivation causes a TST response which is equivalent in magnitude to that induced by precipitating withdrawal with naloxone. This effect of 2DG appears to be mediated by the brain, since icv administration of 2DG caused a TST response, similar to that induced by naloxone treatment of morphine-dependent rats. Collectively, these data suggest that a TST increase is a component of the response of rats to local brain glucoprivation induced by 2DG.

Role of prostaglandin deficiency in pathogenetic mechanism of gastric lesions induced by indomethacin in rats

The present study was undertaken in rats using 2-deoxy-D-glucose (2DG) as a stimulator of gastric motility and a low dose of indomethacin as a prostaglandin (PG) synthesis inhibitor to investigate the roles of gastric motility and PG deficiency in the pathogenesis of indomethacin-induced gastric lesions. Subcutaneously administered indomethacin at 5 mg/kg did not induce any visible damage in the mucosa within 4 hr, but at 25 mg/kg produced linear hemorrhagic lesions along the long axis of the stomach. 2DG (100 mg/kg/hr), given intravenously, produced linear nonhemorrhagic lesions along the mucosal folds and, in the presence of 5 mg/kg of indomethacin, caused severe hemorrhagic lesions in the same areas of the stomach. Gastric motility was markedly enhanced by both indomethacin (25 mg/kg) and 2DG, while acid output and mucosal blood flow were increased only by the latter. Mucosal PGE2 levels were significantly reduced by indomethacin (25 mg/kg) but not by 2DG. Indomethacin at 5 mg/kg alone had no or little effect on any parameter except PG levels, which were reduced to similar degrees as caused by 25 mg/kg of the agent. Time-course development of the lesions was closely associated with those changes in gastric motility after administration of indomethacin (25 mg/kg) and 2DG. These results suggest that the enhanced gastric motility is, by itself, sufficient to induce damage (nonhemorrhagic) in the mucosa and that a PG deficiency alone does not induce any damage but is required for further extension to hemorrhagic lesions of nonhemorrhagic ones that are initially induced by enhanced gastric motility.(ABSTRACT TRUNCATED AT 250 WORDS)

Binocular competition affects the pattern and intensity of ocular activation columns in the visual cortex of cats

The effect of binocular competition on the development of ocular activation columns in areas 17 and 18 of cats was studied using the 14C-2-deoxyglucose (14C-2DG) technique to visualize the regions of cortex activated by one eye in cats reared with equal alternating monocular exposure (equal AME), unequal AME, or monocular deprivation (MD). The average size of the ocular activation columns of the eye stimulated during administration of 2DG was positively correlated with the competitive advantage during rearing. In order of increasing percentage of visual cortex activated, the eyes were (1) deprived eye of MD cats, (2) less experienced eye of unequal AME cats, (3) either eye of equal AME cats, (4) more experienced eye of unequal AME cats, and (5) experienced eye of MD cats. In area 17, the shape of the activation columns also was affected by the relative experience of the eye. The columns of the deprived eye of MD cats were widest in layer IV, where they were about the same width as those of the less experienced eye of the unequal AME cats; in other layers they were narrower, sometimes disappearing altogether. In contrast, the activation columns of the less experienced eye of the unequal AME cats were about the same width in all layers. These results suggest that when one eye is placed at a severe disadvantage and receives no patterned input, as in MD, both geniculocortical connections and intracortical connections may be disrupted, but when the disadvantage is less, as in unequal AME, only the geniculocortical connections are disrupted. Binocular competition also affected the intensity of activation within columns in area 17. We used video densitometry to determine ratios of the amount of label in cortical and thalamic structures. Both the ratio of label in area 17 to that in the lateral geniculate nucleus (LGN) and the ratio of label in the binocular segment of area 17 to that in the monocular segment were significantly less for the deprived eye of MD cats than for any other group. These results suggest that even within the smaller activation columns, deprived geniculocortical afferents are relatively ineffective at driving cortical cells. This finding is consistent with earlier reports that the synapses from the deprived pathway are both morphologically abnormal and reduced in number. The cortical labeling for the less experienced eye of the unequal AME cats and the experienced eye of the MD cats were also significantly less than that in equal AME cats.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of 2-deoxy-D-glucose on food and water intake and body temperature in rats

Comparisons between early daytime and early nighttime effects of 2-deoxy-D-glucose (2DG) injections on food and water intake and rectal temperature were made. Food intake was significantly enhanced by 2DG injections regardless of the phase of the light cycle. In the daytime, water intake was increased by a lower dose of 2DG (200 mg/kg, IP) but there was no further increase at a higher dose (400 mg/kg). At night, the lower dose of 2DG had no effect on water intake but the higher dose suppressed the water intake normally associated with feeding. Administration of 2DG reduced preprandial rectal temperature in a dose dependent fashion in both phases of the light cycle. However, preprandial rectal temperatures were decreased more at night than during the daytime after injection of the higher dose of 2DG. Therefore, 2DG-induced hypothermia is dependent on both the dose of 2DG injected and the phase of the light cycle in which glucoprivation is produced. Furthermore, below a certain level of body temperature, rats markedly reduced drinking behavior while maintaining but not increasing their feeding response to 2DG-induced glucoprivation. These results suggest that behaviors may be directed toward preservations of body temperature in preference to relief of hunger by eating and of thirst by drinking.

Effects of intracellular glucopenia on pulsatile growth hormone secretion: mediation in part by somatostatin.

We examined the effects of 2-deoxy-D-glucose (2DG)-induced intracellular glucoprivation on GH, insulin, and glucose secretory dynamics in freely moving rats bearing chronic intracerebroventricular and intracardiac venous cannulae. Intravenous administration of 2DG (400 mg/kg) caused a severe suppression in amplitude and duration of spontaneous GH surges; plasma GH levels remained significantly depressed for at least 5 h in the presence of marked hyperglycemia. Plasma insulin levels were unchanged. Central administration of a low dose of 2DG (8 mg/10 microliters) also markedly attenuated GH pulse amplitude and raised plasma glucose levels, but this low dose was without effect when injected peripherally, suggesting a central site of action. To elucidate the mechanism(s) mediating the GH suppression response to insufficient glucose we assessed the involvement of the two hypothalamic GH-regulatory peptides, somatostatin (SRIF) and GH-releasing factor (GRF). Passive immunization of 2DG-treated rats with a specific SRIF antiserum (AS) caused an initial surge of GH release and significant elevation of both trough and mean 6-h plasma GH levels, compared to 2DG-normal sheep serum controls. However, SRIF AS failed to restore the amplitude of GH pulses to normal levels. Administration of three iv boluses of human GRF (10 micrograms), at 90-min intervals, to 2DG-treated rats resulted in GH release which was variable and time dependent; the magnitude of the first response (1 h after 2DG injection) was significantly less than that of the other two. Immunoneutralization with SRIF AS eliminated this difference and significantly enhanced human GRF-induced GH release. These results demonstrate that intracellular glucopenia is a potent inhibitor of pulsatile GH secretion in the rat and that this response is mediated, in part, by an increase in SRIF release. While the present findings are compatible with the hypothesis that glucoprivation induces an acute SRIF release, only a partial role for SRIF is indicated in this response. The longer lasting suppression of GH pulses observed after glucose deprivation may be due to decreased output of GRF from the hypothalamus.

Naloxone decreases centrally induced hyperglycemia in dogs. Evidence for an opioid role in glucose homeostasis.

Intracerebroventricular (ICV) instillation of morphine and beta-endorphin causes centrally induced hyperglycemia. Locally active, endogenous opioids in the central nervous system may, therefore, also be involved in the elevation of blood sugar. This possibility was tested by examining the glucoregulatory response to central glucoprivation induced by ICV administration of 2-deoxy-D-glucose (2DG) in dogs. Administration of 2DG resulted in a rise in plasma glucose and immunoreactive glucagon (IRG) of 108 +/- 19 mg/dl and 70 +/- 20 pg/ml, respectively. These changes were attenuated by the simultaneous central infusion of the opiate antagonist naloxone: plasma glucose levels increased by 77 +/- 14 mg/dl and IRG by 43 +/- 3 pg/ml, both significantly different from the effect of 2DG alone (P less than 0.05-0.01). These findings suggest that opiate receptors participate in the counterregulatory response to central glucoprivation. They also provide a mechanism by which endogenous opioid peptides may play a role in the central regulation of glucose homeostasis.

Gastric antral ulcers produced by the combined administration of indomethacin with 2-deoxy-D-glucose in the rat

The influence of 2-deoxy-D-glucose (2DG) on indomethacin ulcers was studied in rats. 2DG (200 mg/kg i.v.) produced large round ulcers in the lesser curvature of the antrum and aggravated lesions of the corpus 6 h after treatments in indomethacin (40 mg/kg i.p.)-treated rats. Insulin (5 units/kg i.v.) also produced gastric antral ulcers similarity to 2DG. Antral ulcers were revealed rather clearly 48 h after the administration of indomethacin and 2DG when the corpus lesion index was reduced. 2DG or insulin had only a slight influence on the severity of other experimental gastric ulcers. Peripheral gastric secretagogues, bethanechol (1 mg/kg s.c. ×2) or histamine (10 mg/kg s.c. ×2) did not produce antral ulcers at the gastric secretory dose in the indomethacin-treated rats. High dose of atropine (1.0 and 10 mg/kg s.c.) prevented gastric antral ulcers. The combined administration of indomethacin with 2DG produced gastric antral ulcers similar to human gastric ulcers in rats. The combination of gastric acid secretion, vagus nerve stimulation and some other factors may be involved in gastric antral ulcers produces in rats.

Comparison of the Effects of 2-Deoxyglucose and Immobilization on Plasma Levels of Catecholamines and Corticosterone in Awake Rats

In rats, both forced immobilization and 2-deoxyglucose (2DG) administration evoke increases in sympatho-adrenal medullary release of catecholamines and adrenal cortical secretion of corticosterone. To examine the specificity and mediation by the central nervous system of these responses, plasma levels of epinephrine (from the adrenal medulla), norepinephrine (from sympathetic nerves), and corticosterone were determined during immobilization and after ip or intracerebroventricular administration of 2DG. After 2DG, plasma levels of epinephrine reached a peak within 15 min, while those of corticosterone were maximal at about 1 h. There was a clear relationship between dose of 2DG and the increases in epinephrine and corticosterone, but plasma levels of norepinephrine were increased only at the highest dose (1000 mg/kg) of 2DG. Severing the splanchnic nerve prevented the elevation in levels of epinephrine but did not alter the increase in corticosterone. The dose of 2DG (500 mg/kg) which elicited the same cor...

Glucose inhibition of the glucose-sensitive neurone in the rat lateral hypothalamus.

IT is generally accepted that the lateral hypothalamic area (LH) and ventromedial nucleus (VMH) have a reciprocal relationship in the control of feeding behaviour1–3, and that some neurones in these regions are sensitive to levels of glucose in the blood4,5 or to electro-osmotically applied glucose6. We have demonstrated that although about one-third of the VMH neurones increased their activity when glucose was applied, there are neurones in LH which are specifically inhibited by it. These neurones are activated by direct applications of insulin, 2-deoxy-D-glucose and 3-O-methyl-D-glucose7. Booth8 demonstrated that the injection of 1 µl of 5% D-glucose in the LH blocked insulin-induced eating. More recently Colin-Jones and Himsworth9 reported that an injection of 2-deoxy-D-glucose (2DG) into the LH causes a marked increase in gastric acid secretion and attributed it to the lack of metabolisable glucose in the LH neurones. The fact that the specific glucose-sensitive cells which are inhibited by glucose exist only in LH has been highlighted in a recent report in which gastric secretion induced by the peripheral administration of 2DG in the cat was blocked by specific and discrete lesions in the lateral hypothalamus10. Here we report that the inhibition of LH neurones induced by direct application of glucose is the result of membrane hyperpolarisation and possibly results from the activation of the sodium pump causing an increased extrusion of internal sodium.

A study of gluconeogenesis by the administration of 2-deoxyglucose. I

2-Deoxyglucose (2DG) an inhibitor of glucose metabolism, 1 induced hyperglycemia and increased endogenic gluconeogenesis. These effects are seen 5–10 minutes after the administration of 2DG. Two hours later an increased liver glycogen content was found. A rise in ninhydrin-reactive-substances was observed in serum and muscle during the first 20 minutes after 2DG administration. This was followed by a decline. A constant rise in urea excretion was detected beginning 30 minutes after the administration of 2DG. The effect of 2DG was not seen in anesthetized rats. On the other hand, electrical stimulation of the posterior hypothalamus increased gluconeogenesis. 24 The inhibitory effect of sympathetic blocking of this process depends on the nutritional state of the animal. The adrenals were indispensable to the increase of gluconeogenesis. A rise in gluconeogenesis was demonstrated 15 minutes after glucagon administration. The mechanism of acute gluconeogenesis following administration of 2DG is discussed.

A study of gluconeogenesis by the administration of 2-deoxyglucose. II

In eviscerated nephrectomized rats administration of 2-deoxyglucose, an inducer of gluconeogenesis, 1 was not followed by a rise of blood amino acid level. It seems therefore that the onset of protein catabolism is a consequence of previous changes in the liver metabolism. Ten minutes after the administration of 2DG, the rate of α amino isobutyric acid accumulation in the liver was not elevated. The activity of glucose 6-phosphatase was unchanged during the first 4 hours, but tyrosineketoglutarate transaminase activity rose after 30 minutes. Prior treatment with inhibitors of protein synthesis, actinomycin D or ethionine does not alter the gluconeogenetic responses in the first 4 hours. It seems that de novo enzyme synthesis is not involved in the initial regulation of gluconeogenesis.