Simultaneous NMR microdialysis study of brain glucose metabolism in relation to fasting or exercise in the rat.

To study the impact of exercise or fasting and of subsequent glucose supplementation on glucose metabolism in rats, a spectrophotometric method was used to determine peripheral blood glucose; a technique associating (1)H-NMR spectroscopy and cortical microdialysis was also used to observe intra- plus extracellular and extracellular brain glucose variations, respectively. Compared with control animals (204 +/- 19 microM in dialysate, n = 10), exercise increased brain extracellular glucose levels to 274 +/- 22 microM (n = 8; P < 0.05), whereas fasting induced a drop in glucose levels down to 140 +/- 9 microM (n = 8; P < 0.05). After fasting, glucose supplemented by infusion increased glycemia from 7.4 +/- 0.4 to 19.9 +/- 0.8 mM (n = 10; P < 0.001), as well as extracellular and extra- plus intracellular brain glucose to 263 +/- 20% (n = 8; P < 0.001) and 342 +/- 28% (n = 8; P < 0.001), respectively, over basal for that group. After exercise, a similar infusion increased glycemia from 7. 3 +/- 0.3 to 16.8 +/- 1.1 mM (n = 10; P < 0.001), as well as extracellular and extra- plus intracellular brain glucose to 178 +/- 19% (n = 8; P < 0.001) and 244 +/- 20% (n = 8; P < 0.001), respectively, over basal for that group. These results confirmed the existence of a link between glucose level variations in peripheral and cerebral areas but also showed that exercise increased extracellular brain glucose levels despite peripheral hypoglycemia, suggesting a specific regulation mechanism of cerebral glucose metabolism during exercise.

Effect of modafinil on cerebral blood flow of anaesthetised rats. Comparison with amphetamine.

This experiment compares the cardio- and cerebrovascular effects of modafinil and amphetamine administered to rats. Injections of 300 mg/kg and 600 mg/kg modafinil i.p. had no major effect. In contrast, injection of D-amphetamine sulfate (5 mg/kg i.v.) induced a long-lasting rise in heart rate and in mean arterial blood pressure (MABP). Amphetamine administration also elicited a 70-min-long increase in cortical cerebral blood flow which was proportional to the increase in MABP. We conclude that, contrary to amphetamine, modafinil has no effect on perfusion in the cerebral cortex of anaesthetised rats.

Functional magnetic resonance imaging of mental strategy in a simulated aviation performance task.

BACKGROUND: The objective of this study was to analyze the sensory and cognitive functions associated with activated brain regions characterizing mental strategy relative to degree of expertise in aviation-related tasks. METHODS: We used echo-planar functional magnetic resonance imaging (fMRI) technique to examine brain activity in expert pilots (n = 6) compared with novice pilots (n = 6) during performance of a simulated aviation track-following task at 200 knots vs. 100 knots. RESULTS: Expert pilots showed reduced activity in visual and motor regions that contrasted with predominant activation within anterior structures including the frontal and prefrontal cortices; structures involved in visual working memory, planning, selective attention and decision making functions. Novice pilots showed widespread activation of anterior and posterior brain structures, with a rise in activity in the visual, parietal and motor cortices as task difficulty increased. CONCLUSIONS: A high level of performance in the track-following task related to a high degree of expertise in the aviation field. This corresponded to experts performing perceptual and mnemonic processing through a network of specialized functions from visual through multiple prefrontal areas. By contrast, the novice pilots predominantly show activity associated with non-specific perceptual processing and without subsequent representation of selective information in working memory.

Effects of GABA-transaminase inhibition on brain metabolism and amino-acid compartmentation: an in vivo study by 2D 1H-NMR spectroscopy coupled with microdialysis.

The aim of this work was to study the neurochemical effects in the brain of GABA-transaminase inhibition by systemic administration of gabaculine (100 mg/kg, i.a.) in the rat. In order to investigate neurotransmitter and related amino-acid compartmentation and metabolism, we have developed an original tool: the coupling, in vivo, on the same animal, of 2D COSY 1H-NMR spectroscopy with intracerebral microdialysis. The main result is a continuous increase in GABA levels, both in the intracellular compartment (up to 3000+/-450%; P<0.001) and extracellular compartment (up to 808+/-82%; P<0.01) at the sixth hour. The intracellular increase in GABA level became significant at the first hour following gabaculine administration, whereas the extracellular level increased as of the second hour, probably indicating that accumulation of GABA in nerve endings precedes its release in synaptic clefts. Moreover, the levels of the excitatory amino acids, glutamate and aspartate, were decreased both in the intra- and extracellular compartments, thus enhancing sedative effects of the drug. We also observed a decrease in the global energetic creatine-phosphocreatine pool, which also could be related to the sedative properties of gabaculine, measurable by the diminution of cortical electrical activity and mean arterial blood pressure. Finally, the coupling between 2D 1H-NMR spectroscopy and intracerebral microdialysis appears to be an original tool for investigating the cerebral metabolic effects induced by pharmacological agents, in situ, in living animals.

Effects of a vigilance-enhancing drug, modafinil, on rat brain metabolism: a 2D COSY 1H-NMR study.

The effects of modafinil, a vigilance-enhancing drug, on brain metabolism were investigated directly in situ by the 2D COSY 1H-NMR spectroscopy in anesthetized rats. Modafinil (600 mg/kg, i.p.) induced significant increases in both aspartate (72% +/- 15%) and glutamate-glutamine pool (28% +/- 8%) simultaneously with increases in inositol (51% +/- 19%) and creatine-phosphocreatine pool (47% +/- 14%) in comparison with control values (P < 0.05; n = 5). These results suggest that the awakening properties of modafinil could be mediated by metabolic activation.

Physical performance and metabolic changes induced by combined prolonged exercise and different energy intakes in humans.

The purpose of this study was to evaluate the effects on physical performance of three levels of energy intake during a 5-day period of prolonged physical exercise and relative sleep deprivation. A group of 27 male soldiers were randomly assigned to three groups receiving either 1800 kcal.24 h-1 (7560 kJ, LC), 3200 kcal.24 h-1 (13440 kJ, MC) or 4200 kcal.24 h-1 (17,640 kJ, HC). They took part in a 5-day combat course (CC) of heavy and continuous physical activities, with less than 4 h sleep per day. Performance capacity was tested just before and at the end of CC. Maximal oxygen uptake (VO2max) was determined during an exhausting incremental exercise test on a cycle ergometer. Anaerobic performance was measured from the time during which exercise could be maintained at supra maximal loads on a cycle ergometer. After CC, the subjects receiving LC exhibited a 14% decrease in power output at exhaustion in the incremental exercise test [from 325 (SEM 8) to 278 (SEM 9) W, P < 0.001] and a significant decrease in VO2max of 8% [from 3.74 (SEM 0.06) to 3.45 (SEM 0.05) 1.min-1, P < 0.05]. The remaining two experimental groups demonstrated the same mechanical and metabolic performances on days 1 and 5. Anaerobic performance was not influenced by energy intake and the field course. Blood samples were obtained at rest on days 1 and 5. At the end of CC, the data demonstrated a significant decrease in blood glucose concentrated ion (P < 0.01) for LC diet only.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of type and structure of complex carbohydrates response to physical exercise.

To examine the level of oxidation between different carbohydrate foodstuffs ingested one hour before exercise, three experiments were conducted in men. They performed a series of exercise tests of two hours duration at 60% VO2max preceded in experiment I by ingestion of one of five isocaloric (836 kJ) successive meals of bread, potatoes, rice, spaghetti, or glucose; in experiment II, by either spaghetti or glucose, both naturally 13C enriched; in experiment III, by one of four 13C labelled meals containing starches differing in their proportion of amylose and amylopectin and in their culinary preparation. Results show: 1) The following glucose and insulin response from the highest to the lowest was: glucose > potatoes > bread > rice > spaghetti and after 30 min of exercise a significantly lower blood glucose concentration observed after glucose and potato diets compared to the rice and spaghetti meals. The level of 13CO2 production from the food ingested in experiments II and III was expressed in terms of Atom Percent Excess (APE). Data suggests that spaghetti is oxidized to a lesser degree than glucose. The comparison between starches shows that gelatinized amylopectin is metabolized to the same extent as glucose when there is a progressive decline in the level of oxidation from gelantinized amylose and crude amylopectin to crude amylose.

Effects of protein supplementation during prolonged exercise at moderate altitude on performance and plasma amino acid pattern.

The effects of two levels of protein intake on muscle performance and energy metabolism were studied in humans submitted to repeated daily sessions of prolonged exercise at moderate altitude. For this purpose, 29 healthy males, were exposed to seven successive stages of ski-mountaineering at altitudes between 2500 and 3800 m, and to an isocaloric diet (4000 kcal.day-1, 16,760 kJ.day-1) with either 1.5 g.kg-1.day-1 (C group, n = 14), or 2.5 g.kg-1.day-1 (PR group, n = 15) protein intake. Measurements made after the ski-mountaineering programme did not show any change in body mass. The peak torque during maximal isometric voluntary contraction (MVC) of the quadriceps muscle was unaffected by the repeated exercises, whereas the endurance time at 50% MVC was decreased in PR subjects (-26.8%, P < 0.001). Increased levels of both free fatty acids (+ 147%, P < 0.001) and glycerol (+ 170%, P < 0.001) observed in C subjects would suggest that lipolysis was enhanced after the repeated exercise. The plasma amino acid pattern was altered after completion of the ski-mountaineering programme; the plasma concentration of the three branched-chain amino acids (BCAA) was significantly decreased in C subjects, whereas the higher level of protein intake (PR group) greatly minimized the exercise-induced decrease in serum BCAA.

Influence of glucose, medium- and long-chain triglyceride gastric loads and forced exercise on food intake and body weight in rats.

The purpose of this study was to examine the effect of oesophageal loads of glucose, medium (MCT)-and long-chain (LCT) triglycerides, plus treadmill exercise on food intake and body weight in rats. On test days, male rats were administered a gastric aqueous solution of glucose, MCT, LCT or water via an oesophageal tube. One hour later, the animals were forced to run on a treadmill for two hours at a speed of 20 m/min at 0% grade. At the beginning of the 12-hour dark cycle (at 7 p.m.) runners were returned to their cages. On control days, the same gastric loads were administered, but the animals remained in their cages. Food intake was continuously measured during both the dark and light periods. A reduction in body weight and total food intake was found after exercise. The food intake suppressing effect of exercise was seen in the first hours of the dark period. Following MCT and LCT oil stomach loads FI decrease was comparable but the latency of the effect varied. Stomach loads of MCT oil induced a reduction in FI within the 0-3 h of food availability whereas LCT oil suppressed intake during the 3-6-h dark period. This could be explained by their different metabolite fate.

Influence of polyunsaturated fatty acid diet on the hemorrheological response to physical exercise in hypoxia.

Several studies have shown that hemorrheological parameters are modified by physical exercise and exposure to altitude hypoxia. These changes result in a decrease in red cell deformability (RCD). Similarly, it has been shown that a daily dietary fish oil supplement increases RCD. The purpose of this study was to evaluate the influence of fish oil diet on RCD after exercise. Fourteen male subjects (19-38 years old) were divided into two groups. The first group ate a "standard diet" rich in saturated lipids; the second group received a daily amount of 6 g of MaxEPA fish oil for 6 weeks. Before the 6 weeks of experimental nutrition, and just after this period, both groups were submitted to two physical exercises of 1 h cycling at 70% of their VO2max. One test was performed at sea level, the other at a simulated altitude of 3000 m in a hypobaric chamber. Blood samples were drawn before and after exercise and used to evaluate: (1) RCD by filtration on polycarbonate membrane, (2) plasma viscosity, and (3) erythrocyte phospholipid composition. Energy charge of red cell was evaluated by ATP/AMP/ADP and two to three DPB assays. Gas liquid chromatography indicated an increase in n-3 PUFA membrane erythrocyte composition. In the control group, RCD decreased by an average of 53% after exercise under hypoxic conditions and was unchanged after the same exercise at sea level. MaxEPA diet suppresses the decrease in RCD observed after hypoxic exercise. These results indicate a decrease in RCD under the combined effects of exercise and hypoxia, which is prevented by 6 weeks of fish oil supplement.

Oxidation of corn starch, glucose, and fructose ingested before exercise.

The purpose of this study was to compare the metabolic and endocrine responses, and the amounts of exogenous carbohydrate oxidized, during prolonged moderate cycle ergometer exercise (120 min, 60% VO2max), preceded by ingestion of 13C enriched glucose (G), fructose (F), or pure corn starch (S) (1,592 kJ ingested with 400 ml of water, 60 min before the beginning of exercise) in six healthy young male subjects. Plasma glucose and insulin concentrations significantly increased in response to G and S feeding. The high plasma insulin values resulted in a significant transient reduction in plasma glucose concentration in the first hour of exercise and blunted the response of plasma free fatty acid and glycerol concentrations, when compared to the values observed with F ingestion, which did not modify plasma glucose or insulin concentrations. Over the 2 h exercise period, the percentages of exogenous G (67 +/- 9%) and S (73 +/- 8%) oxidized were not significantly different but were significantly higher than the percentage of exogenous F oxidized (54 +/- 6%). These results confirm that 1) exogenous F is less readily available for oxidation than G or S and 2) pure corn starch does not offer any advantage over glucose as a pre-exercise meal.

Post-exercise glycogen resynthesis in trained high-protein or high-fat-fed rats after glucose feeding.

This study examined the effect on glycogen resynthesis during recovery from exercise of feeding glucose orally to physically trained rats which had been fed for 5 weeks on high-protein low fat (HP), high-protein/long-chain triglyceride (LCT) or high carbohydrate (CHO) diets. Muscle glycogen remained low and hepatic gluconeogenesis was stimulated by long-term fat or high-protein diets. The trained rats received, via a stomach tube, 3 ml of a 34% glucose solution immediately after exercise (2 h at 20 m.min-1), followed by 1-ml portions at hourly intervals until the end of the experiments. When fed glucose soleus muscle glycogen overcompensation occurred rapidly in the rats fed all three diets following prolonged exercise. In LCT- and CHO-fed rats, glucose feeding appeared more effective for soleus muscle repletion than in HP-fed rats. The liver demonstrated no appreciable glycogen overcompensation. A complete restoration of liver glycogen occurred within a 2- to 4-h recovery period in the rats fed HP-diet, while the liver glycogen store had been restored by only 67% in CHO-fed rats and 84% in LCT-fed rats within a 6-h recovery period. This coincides with low gluconeogenesis efficiency in these animals.

Effects of long-term feeding of high-protein or high-fat diets on the response to exercise in the rat.

The aim of this work was to find by which mechanisms an increased availability of plasma free fatty acids (FFA) reduced carbohydrate utilization during exercise. Rats were fed high-protein medium-chain triglycerides (MCT), high-protein long-chain triglycerides (LCT), carbohydrate (CHO) or high-protein low-fat (HP) diets for 5 weeks, and liver and muscle glycogen, gluconeogenesis and FFA oxidation were studied in rested and trained runner rats. In the rested state the hepatic glycogen store was decreased by fat and protein feeding, whereas soleus muscle glycogen concentration was only affected by high-protein diets. The percentage decrease in liver and muscle glycogen stores, after running, was similar in fat-fed, high-protein and CHO-fed rats. The fact that plasma glucose did not drastically change during exercise could be explained by a stimulation of hepatic gluconeogenesis: the activity of phosphoenolpyruvate carboxykinase (PEPCK) and liver phosphoenolpyruvate (PEP) concentration increased as well as cyclic adenosine monophosphate (AMPc) while liver fructose 2,6-bisphosphate decreased and plasma FFA rose. In contrast, the stimulation of gluconeogenesis in rested HP-, MCT- and LCT-fed rats appears to be independent of cyclic AMP.

Metabolic effects of glucose, medium chain triglyceride and long chain triglyceride feeding before prolonged exercise in rats.

The purpose of this study was to test the hypothesis that oral ingestion of lipids could increase endurance by slowing the rate of glycogen depletion. Trained rats were killed after a 2 h run on a rodent treadmill, following an intragastric infusion of water, glucose, medium chain triglycerides (MCT) or long chain triglycerides (LCT). Glucose and triglycerides were administered in equicaloric concentrations (50 kJ). The results show that oral ingestion of lipids (MCT or LCT) did not reduce glycogen depletion in liver, heart or skeletal muscle after exercise whereas the fat diet increased muscle and heart glycogen stores in resting conditions. In contrast, glucose feeding induced a significant sparing effect on endogenous carbohydrate utilization and reduced physical exercise lipolysis. These data indicated, firstly, that enhanced lipid availability induced by a single lipid meal before exercise was not able to modify the glycogen depletion occurring after exercise and, secondly, that the glucose/fatty acid cycle was not effective in these conditions. The comparison between lipids indicated that the effect on glycogen use of MCT did not differ from that of LCT, and did not seem to be of any particular importance during physical exercise.

Metabolic and hormonal responses to lipid and carbohydrate diets during exercise in man.

Nine healthy subjects were studied to determine their performance and the metabolic and hormonal responses to prolonged exercise after ingestion of a carbohydrate or a lipid diet. Subjects exercised on a bicycle ergometer (60% VO2max) until exhaustion four times at weekly intervals. The exercise test was performed 1 h after ingestion of three different isocaloric meals (400 Kcal) containing either glucose, medium-chain triglycerides (MCTs) or long-chain triglycerides (LCTs). The fourth test was performed after a night fast. The metabolism of these nutriments was followed using [U-13C]glucose, [1-13C]octanoate, and [1-13C]palmitate added as tracers. The average work time was comparable whatever nutriment used (116 +/- 11 min). Oxidation of the ingested nutriment over this period was 80% for glucose, 45% for MCTs, and 9% for LCTs. Glucose ingestion produced an early insulin peak associated at the end of the exercise with a lower glycemia compared to the fat diets. After MCT ingestion, an increase in ketone bodies was observed. Catecholamine response to physical exercise was decreased by all the meals when compared to fasting. Thus, we conclude that a different lipid meal, MCTs, or LCTs, compared to glucose feeding, do not modify exhaustion time in spite of differences in hormonal and metabolic responses.

Development and regulation of ketogenesis in hepatocytes isolated from newborn rats.

The development of fatty acid metabolism was studied in isolated hepatocytes from newborn rats. Ketone-body production from oleate is increased 6-fold between 0 and 16 h after birth. This increase is related to an enhanced beta-oxidation rather than to a channeling of acetyl-CoA from the tricarboxylic acid cycle to ketone-body synthesis. The increase in oleate oxidation is not related to a decreased esterification rate, as the latter is already low at birth and does not decrease further. At birth, lipogenic rate is 2-3-fold lower than in fed adult rats and it decreases to undetectable values in 16 h-old rats. A 90% inhibition of lipogenesis in hepatocytes of newborn rats (0 h) by glucagon and 5-(tetradecyloxy)-2-furoic acid does not lead to an increased oxidation of non-esterified fatty acids. This suggests that the inverse relationship between lipogenesis and ketogenesis in the starved newborn rat is not responsible for the switch-on of fatty acid oxidation at birth. Moreover, ketogenesis from octanoate, a medium-chain fatty acid the oxidation of which is independent of carnitine acyltransferase, follows the same developmental pattern at birth as that from oleate.

Relationship between ketogenesis and gluconeogenesis in isolated hepatocytes from newborn rats.

In hepatocytes from 1-day-old rats, active gluconeogenesis occurs in parallel with active ketogenesis, although the carbon atoms of non-esterified fatty acids do not participate in glucose synthesis. Once a significant ketogenesis is established, a further increase does not enhance gluconeogenesis. Indeed, octanoate is more ketogenic than oleate, but stimulates gluconeogenesis to a similar extent.

Evidence that stimulation of glucose metabolism by insulin is not altered in isolated soleus muscle of pregnant rats.

Various concentrations of insulin stimulated to the same extent glucose transport and metabolism in incubated soleus muscle of virgin and 19-day-pregnant rats. This suggests that the resistance to insulin that occurs during pregnancy in vivo does not result from an intrinsic defect in skeletal muscles.

[Insulin resistance during pregnancy (author's transl)]. / Résistance à l'ínsuline pendant la gestation.

Whereas insulin secretion in response to IV glucose is markedly increased between day 17 and 21 of gestation in the Rat, glucose disappearance rate remains unchanged. This suggests that maternal tissues become less sensitive to endogenous insulin. Glucose kinetics (glucose production, utilization and clearance) in response to various doses of IV insulin have been studied in 19 day pregnant and virgin rats by using [6-3H] glucose. With a supramaximal dose of insulin (4 U/kg body wt) no difference was found between pregnant and virgin rats. In contrast, with the two inframaximal doses of insulin (0.15 & 0.05 U/kg) glucose production was not decreased in pregnant rats whereas it was inhibited by 36 and 13% in virgin rats. Moreover the increase in glucose clearance was higher in virgin (186 & 146 %) than in pregnant rats (160 & 124 %). This suggests that decreased sensitivity to insulin in late pregnancy involves both liver and peripheral tissues. In vitro, glucose transport and metabolism were stimulated to the same extent by insulin in soleus muscles of pregnant and virgin rats. This suggests that insulin resistance in pregnancy could result from circulating antagonists of insulin (FFA, progesterone, placental lactogen).