Response of glutamine metabolism to glutamine-supplemented parenteral nutrition.

BACKGROUND: Increasing evidence suggests that glutamine is important for the function of many organ systems and supports the use of glutamine-enriched total parenteral nutrition (TPN) during severe illness. However, the effect of prolonged glutamine supplementation on glutamine kinetics has not been studied. OBJECTIVE: We investigated the effect of 8-10 d of TPN enriched with glutamine dipeptides on glutamine kinetics. DESIGN: Twenty-three preoperative patients were randomly allocated to receive either TPN enriched with glutamine dipeptides (60 micromol glutamine*kg body wt(-1)*h(-1)) or isonitrogenous, isoenergetic, glutamine-free TPN. A primed, continuous, 6-h intravenous infusion of L-[5-(15)N]glutamine and L-[1-(13)C]leucine was given before (baseline) and 8-10 d after the TPN solutions were administered. Baseline measurements were performed after a 40-h administration of a standard solution of glucose and amino acids (no glutamine). RESULTS: Glutamine-enriched TPN increased the total appearance rate of glutamine (P: < 0.05) but did not inhibit or increase the endogenous appearance rate. The standard TPN solution also increased the glutamine appearance rate (P: < 0.05), but the change was much smaller than in the glutamine-supplemented group (P: < 0.01). The plasma glutamine concentration did not rise significantly during either treatment, suggesting increased tissue glutamine utilization, especially in the glutamine-supplemented group. CONCLUSION: In view of the enhanced glutamine requirements in response to trauma and disease by tissues such as those of the gut, the immune system, and the liver, increased glutamine availability during glutamine-enriched TPN may be beneficial preoperatively in patients with gastrointestinal disease.

Plasma insulin responses after ingestion of different amino acid or protein mixtures with carbohydrate.

BACKGROUND: Protein induces an increase in insulin concentrations when ingested in combination with carbohydrate. Increases in plasma insulin concentrations have been observed after the infusion of free amino acids. However, the insulinotropic properties of different amino acids or protein (hydrolysates) when co-ingested with carbohydrate have not been investigated. OBJECTIVE: The aim of this study was to define an amino acid and protein (hydrolysate) mixture with a maximal insulinotropic effect when co-ingested with carbohydrate. DESIGN: Eight healthy, nonobese male subjects visited our laboratory, after an overnight fast, on 10 occasions on which different beverage compositions were tested for 2 h. During those trials the subjects ingested 0.8 g*kg(-)(1)*h(-)(1) carbohydrate and 0.4 g*kg(-)(1)*h(-)(1) of an amino acid and protein (hydrolysate) mixture. RESULTS: A strong initial increase in plasma glucose and insulin concentrations was observed in all trials, after which large differences in insulin response between drinks became apparent. After we expressed the insulin response as area under the curve during the second hour, ingestion of the drinks containing free leucine, phenylalanine, and arginine and the drinks with free leucine, phenylalanine, and wheat protein hydrolysate were followed by the largest insulin response (101% and 103% greater, respectively, than with the carbohydrate-only drink; P < 0.05). CONCLUSIONS: Insulin responses are positively correlated with plasma leucine, phenylalanine, and tyrosine concentrations. A mixture of wheat protein hydrolysate, free leucine, phenylalanine, and carbohydrate can be applied as a nutritional supplement to strongly elevate insulin concentrations.

Maximizing postexercise muscle glycogen synthesis: carbohydrate supplementation and the application of amino acid or protein hydrolysate mixtures.

BACKGROUND: Postexercise muscle glycogen synthesis is an important factor in determining the time needed to recover from prolonged exercise. OBJECTIVE: This study investigated whether an increase in carbohydrate intake, ingestion of a mixture of protein hydrolysate and amino acids in combination with carbohydrate, or both results in higher postexercise muscle glycogen synthesis rates than does ingestion of 0.8 g*kg(-)(1)*h(-)(1) carbohydrate, provided at 30-min intervals. DESIGN: Eight trained cyclists visited the laboratory 3 times, during which a control beverage and 2 other beverages were tested. After the subjects participated in a strict glycogen-depletion protocol, muscle biopsy samples were collected. The subjects received a beverage every 30 min to ensure ingestion of 0.8 g carbohydrate*kg(-)(1)*h(-)(1) (Carb trial), 0.8 g carbohydrate*kg(-)(1)*h(-)(1) plus 0.4 g wheat protein hydrolysate plus free leucine and phenylalanine*kg(-)(1)*h(-)(1) (proven to be highly insulinotropic; Carb + Pro trial), or 1.2 g carbohydrate*kg(-)(1)*h(-)(1) (Carb + Carb trial). After 5 h, a second biopsy was taken. RESULTS: Plasma insulin responses in the Carb + Pro and Carb + Carb trials were higher than those in the Carb trial (88 +/- 17% and 46 +/- 18%; P < 0.05). Muscle glycogen synthesis was higher in both trials than in the Carb trial (35. 4 +/- 5.1 and 44.8 +/- 6.8 compared with 16.6 +/- 7.8 micromol glycosol units*g dry wt(-)(1)*h(-)(1), respectively; P < 0.05). CONCLUSIONS: Addition of a mixture of protein hydrolysate and amino acids to a carbohydrate-containing solution (at an intake of 0.8 g carbohydrate*kg(-)(1)*h(-)(1)) can stimulate glycogen synthesis. However, glycogen synthesis can also be accelerated by increasing carbohydrate intake (0.4 g*kg(-)(1)*h(-)(1)) when supplements are provided at 30-min intervals.

Effect of oral glucose on leucine turnover in human subjects at rest and during exercise at two levels of dietary protein.

The aim of this study was to determine the effect of glucose supplementation on leucine turnover during and after exercise and whether variation in the previous dietary protein content modulated this effect. Postabsorptive subjects received a primed constant [1-13C, 15N]leucine infusion for 6 h, after previous consumption of a high (1.8 g kg-1 day-1, HP, n = 16) or low (0.7 g kg-1 day-1, LP, n = 16) protein diet for 7 days. The subjects were studied at rest; during 2 h of exercise, during which half of the subjects from each dietary protocol received 0.75 g kg-1 h-1 glucose (HP + G, LP + G) and the other half received water (HP + W, LP + W); then again for 2 h of rest. Glucose supplementation suppressed leucine oxidation (P < 0.01) by 20% in subjects consuming the high protein diet (58.2 +/- 2.8 micromol kg-1 h-1, HP + G; 72.4 +/- 3.9 micromol kg-1 h-1, HP + W) but not the low protein diet (51.1 +/- 5.9 micromol kg-1 h-1, LP + G; 51.7 +/- 5.5 micromol kg-1 h-1, LP + W), with no difference in skeletal muscle branched-chain 2-oxo acid dehydrogenase (BCOADH) activity between groups. Glucose supplementation did not alter the rate of whole-body protein synthesis or breakdown. The sparing effect of glucose on leucine oxidation appears only to occur if previous protein intake was high. It was not mediated by a suppression of BCOADH fractional activity but may be due to reduced substrate availability.

Glutamine appearance rate in plasma is not increased after gastrointestinal surgery in humans.

The metabolic response to surgical stress is characterized by muscle protein breakdown and mobilization of amino acids and has been postulated to furnish glutamine and other amino acids to the immune system, gut and liver. The present study was undertaken to investigate whether the whole body appearance rate (R(a))(3) of glutamine in plasma is increased after major elective surgery. Fourteen patients (8 males, 6 females) were measured prior to laparotomy and on the second postoperative day. Patients received a primed continuous 6-h infusion of L-[5-(15) N]glutamine and L-[1-(13)C]leucine, and arterial blood samples and muscle biopsies were taken for concentration and enrichment measurements. As expected, the metabolic response to surgery was characterized by a rise in whole body protein breakdown (n = 14, P < 0.001) and a decreased concentration of glutamine in plasma (n = 14, P < 0.001) and muscle (n = 8, P < 0.01). However, these catabolic changes were not reflected by an increase in the plasma R(a) of glutamine: 246 +/- 8 micromol. kg(-1). h(-1) before surgery vs. 241 +/- 10 micromol. kg(-1). h(-1) on the second postoperative day. We conclude that the whole body R(a) of glutamine in plasma is not increased 2 d after elective gastrointestinal surgery. Further studies are warranted to establish whether the lack of an increase in plasma glutamine R(a) provides a rationale for glutamine supplementation.

American College of Sports Medicine roundtable. The physiological and health effects of oral creatine supplementation.

Creatine (Cr) supplementation has become a common practice among professional, elite, collegiate, amateur, and recreational athletes with the expectation of enhancing exercise performance. Research indicates that Cr supplementation can increase muscle phosphocreatine (PCr) content, but not in all individuals. A high dose of 20 g x d(-1) that is common to many research studies is not necessary, as 3 g x d(-1) will achieve the same increase in PCr given time. Coincident ingestion of carbohydrate with Cr may increase muscle uptake; however, the procedure requires a large amount of carbohydrate. Exercise performance involving short periods of extremely powerful activity can be enhanced, especially during repeated bouts of activity. This is in keeping with the theoretical importance of an elevated PCr content in skeletal muscle. Cr supplementation does not increase maximal isometric strength, the rate of maximal force production, nor aerobic exercise performance. Most of the evidence has been obtained from healthy young adult male subjects with mixed athletic ability and training status. Less research information is available related to the alterations due to age and gender. Cr supplementation leads to weight gain within the first few days, likely due to water retention related to Cr uptake in the muscle. Cr supplementation is associated with an enhanced accrual of strength in strength-training programs, a response not independent from the initial weight gain, but may be related to a greater volume and intensity of training that can be achieved. There is no definitive evidence that Cr supplementation causes gastrointestinal, renal, and/or muscle cramping complications. The potential acute effects of high-dose Cr supplementation on body fluid balance has not been fully investigated, and ingestion of Cr before or during exercise is not recommended. There is evidence that medical use of Cr supplementation is warranted in certain patients (e.g.. neuromuscular disease); future research may establish its potential usefulness in other medical applications. Although Cr supplementation exhibits small but significant physiological and performance changes, the increases in performance are realized during very specific exercise conditions. This suggests that the apparent high expectations for performance enhancement, evident by the extensive use of Cr supplementation, are inordinate.

The effect of free glutamine and peptide ingestion on the rate of muscle glycogen resynthesis in man.

The present study investigated previous claims that ingestion of glutamine and of protein-carbohydrate mixtures may increase the rate of glycogen resynthesis following intense exercise. Eight trained subjects were studied during 3 h of recovery while consuming one of four drinks in random order. Drinks were ingested in three 500 ml boluses, immediately after exercise and then after 1 and 2 h of recovery. Each bolus of the control drink contained 0.8 g x kg(-1) body weight of glucose. The other drinks contained the same amount of glucose and 0.3 g x kg(-1) body weight of 1) glutamine, 2) a wheat hydrolysate (26% glutamine) and 3) a whey hydrolysate (6.6% glutamine). Plasma glutamine, decreased by approximately 20% during recovery with ingestion of the control drink, no changes with ingestion of the protein hydrolysates drinks, and a 2-fold increase with ingestion of the free glutamine drinks. The rate of glycogen resynthesis was not significantly different in the four tests: 28 +/- 5, 26 +/- 6, 33 +/- 4, and 34 +/- 3 mmol glucosyl units x kg(-1) dry weight muscle x h(-1) for the control, glutamine, wheat- and whey hydrolysate ingestion, respectively. It is concluded that ingestion of a glutamine/carbohydrate mixture does not increase the rate of glycogen resynthesis in muscle. Glycogen resynthesis rates were higher, although not statistically significant, after ingestion of the drink containing the wheat (21 +/- 8%) and whey protein hydrolysate (20 +/- 6%) compared to ingestion of the control and free glutamine drinks, implying that further research is needed on the potential protein effect.

Glutamine: the pivot of our nitrogen economy?

Glutamine serves as a shuttle of useful nontoxic nitrogen, supplying nitrogen from glutamine-producing (eg, muscle) to glutamine-consuming tissues. True production rates of glutamine are difficult to measure, but probably are less than 60 to 100 g/d for a 70-kg man. During catabolic stress increased amounts of glutamine are released from muscle, consisting of protein derived glutamine, newly synthesized glutamine, and glutamine losses from the intramuscular free pool. The large and rapid losses of free muscle glutamine are difficult to restore, presumably as a result of disturbances in the Na+ electrochemical gradient across the cell membrane. Whereas increased amounts of glutamine are released from muscle, glutamine consumption by the immune system (liver, spleen) also is enhanced. Thus, during catabolic stress changes occur in the flow of glutamine between organs. These changes are not necessarily reflected by alterations in the whole-body appearance rate of glutamine. In contrast with the gut, where glutamine is taken up in a concentration dependent manner, the immune system actively takes up glutamine despite decreased plasma concentrations. Supplementation with glutamine influences uptake by both the gut and the immune system, as evidenced by increased mucosal glutamine concentrations and gut glutathione production. There is evidence suggesting that this improves gut barrier function. Although the benefit of glutamine supplementation is most evident from experimental studies, clinical studies on the effect of glutamine do exist and suggest that glutamine supplementation has beneficial effects with regard to patient outcome.

Amino acid supplements to improve athletic performance.

This review provides a critical evaluation of the metabolic rationale for the use of individual amino acids as nutritional ergogenic (work-generating) aids in athletes. The conclusion is that in contrast to the claims made on sport nutrition products, branched-chain amino acids do not improve endurance performance, that the evidence that glutamine supplements may improve immune function is rather weak, and that the available commercial supplements contain too little arginine to increase growth hormone levels. No studies have been performed to investigate the claim that tyrosine supplements can improve explosive exercise.

Fat metabolism during exercise: a review--part III: effects of nutritional interventions.

By changes in nutrition it is possible to manipulate fat oxidation. It is often theorized that increasing fat oxidation may reduce glycogen breakdown and thus enhance performance. Therefore, the effects of acute, short-term and long-term fat feeding have been subjects of investigation for many years. Ingestion of long-chain triacylglycerols (LCT) during exercise may reduce the gastric emptying rate and LCT will appear in the plasma only slowly. Medium-chain triacylglycerols (MCT) do not have these disadvantages and they are rapidly oxidized. However, the contribution of MCT to energy expenditure is only small because they can only be ingested in small amounts without causing gastrointestinal distress. So at present, fat supplementation in the hours preceding to or during exercise (either long chain or medium chain triacylglycerols) cannot be recommended. High-fat diets and fasting have been suggested to increase fatty acid availability and spare muscle glycogen resulting in improved performance. Both fasting and short term high-fat diets will decrease muscle glycogen content and reduce fatigue resistance. Chronic high-fat diets may provoke adaptive responses preventing the decremental effects on exercise performance. However, at present, there is little evidence to support this hypothesis. Also from a health perspective, caution should be exercised when recommending high-fat diets to athletes.

Effect of carbohydrate supplementation on plasma glutamine during prolonged exercise and recovery.

Muscle glycogen and glucose have been suggested to be carbon-chain precursors for glutamine synthesis in skeletal muscle. Therefore, the aim of the present study is to investigate whether carbohydrate supplementation affects plasma glutamine and other amino acids during exercise and 7 h of recovery. Eight well-trained subjects cycled at an alternating workload of 50 and 80% Wmax until exhaustion (59 to 140 min). During the exercise bout the subjects received either water (control) or a carbohydrate (CHO) drink (83 g CHO x l(-1), 2 ml x kg(-1) per kg body weight every 15 min). Plasma glutamine concentration appeared not to be affected by exercise, as a significant increase was only observed at some points in time during the control test. During recovery, however, plasma glutamine concentration decreased from 682+/-24 and 685+/-19 micromol x l(-1) at exhaustion to 552+/-19 and 534+/-12 micromol x l(-1) after 2 h of recovery for the control and CHO test, respectively. Plasma glutamine concentration returned to pre-exercise values after 7 h of recovery. Alanine concentration increased during exercise in both tests. During the recovery period the concentration of alanine (48%), and total amino acids (23%) decreased below the pre-exercise level. The plasma alanine and the total amino acid concentration was still suppressed after 7 h of recovery. In conclusion, carbohydrate supplementation had neither an effect during exercise nor during recovery on the concentration of plasma glutamine or other amino acids. Exercise, however, causes a substantial decrease in the plasma amino acid concentration during recovery.

Effect of endogenous carbohydrate availability on oral medium-chain triglyceride oxidation during prolonged exercise.

The present study examined the medium-chain triglyceride (MCT) oxidation rate of oral carbohydrate (CHO) + MCT supplements after a glycogen-depletion trial [low glycogen (LG)] and in the glycogen-loaded state [normal-to-high glycogen (HG)]. Eight elite athletes cycled four times 90 min at 50% maximal workload (57% maximal O2 uptake). In two trials, they followed a LG protocol to achieve low-glycogen stores in the leg muscles the evening before the experiment, and in two trials they followed a HG protocol. Subjects received a bolus of 4 ml/kg at the start and 2 ml/kg every 20 min during exercise of either a 15% CHO (long-chain glucose polymer) solution or an equicaloric CHO + MCT suspension. Exogenous MCT oxidation was measured by adding a [1,1,1-13C]trioctanoate tracer to the MCT oil and measuring 13CO2 production in the breath. The results show that 85% of MCT ingested was oxidized in LG and 69% in HG during the 60- to 90-min period. There was no statistically significant difference in MCT utilization between LG and HG. Peak oxidation rates were 0.15 and 0.13 g/min, respectively. MCT contributed 7.6% (LG) and 6.5% (HG) to total energy expenditure during the 60- to 90-min period. Total fatty acid oxidation was significantly elevated in the LG trial but was not influenced by MCT ingestion. Concomitantly, CHO oxidation was reduced in LG but no effect of MCT was observed. We conclude that 1) the contribution of MCT to total energy expenditure was small and 2) strenuous exercise the day before the experiment, followed by a low CHO intake and leading to a low CHO availability, substantially increased total fat oxidation but did not significantly increase MCT oxidation.

Ingestion of branched-chain amino acids and tryptophan during sustained exercise in man: failure to affect performance.

1. An increased uptake of tryptophan in the brain may increase serotoninergic activity and recently has been suggested to be a cause of fatigue during prolonged exercise. The present study, therefore, investigates whether ingestion of tryptophan or the competing branched-chain amino acids (BCAAs) affect performance. Ten endurance-trained male athletes were studied during cycle exercise at 70-75% maximal power output, while ingesting, ad random and double-blind, drinks that contained 6% sucrose (control) or 6% sucrose supplemented with (1) tryptophan (3 g l-1), (2) a low dose of BCAA (6 g l-1) or (3) a high dose of BCAA (18 g l-1). 2. These treatments greatly increased the plasma concentration of the respective amino acids. Using the kinetic parameters of transport of human brain capillaries, BCAA supplements were estimated to reduce brain tryptophan uptake at exhaustion by 8-12%, while tryptophan ingestion caused a 7- to 20-fold increase. Exercise time to exhaustion was not different between treatments (122 +/- 3 min). 3. The data suggest that manipulation of tryptophan supply to the brain either has no additional effect upon serotoninergic activity during prolonged exhaustive exercise or that manipulation of serotoninergic activity functionally does not contribute to mechanisms of fatigue.

Breath 13CO2 background enrichment during exercise: diet-related differences between Europe and America.

A traditional North American diet contains a high percentage of carbohydrates (CHO) derived from C4 plants (maize, sugar cane), whereas a European diet contains primarily CHO derived from C3 plants (potato, sugar beet). The natural 13C enrichment of the first type of CHO is higher than that of the latter type. 13CO2 production from orally ingested C4 plant-derived CHO can, therefore, be used to quantify oxidation rates of orally ingested CHO at rest and during exercise. Recently it has been shown that oxidation rates assessed this way in North Americans should be corrected for an increase in breath background 13CO2 during exercise. We hypothesized that the indicated difference in metabolic origin of CHO would imply that no such correction is required for subjects on a European diet. We therefore studied changes from rest in breath 13CO2 enrichment in Dutch volunteers during cycle ergometry at 65% maximal work load (experiment 1, 2h, 6 subjects) and 70% maximal oxygen uptake (experiment 2, 90 min, 8 subjects) while ingesting water (experiments 1 and 2) and potato starch-derived glucose (experiment 2). Experiment 1 was done before and after careful instruction of the subjects to refrain from nutrient sources potentially containing CHO of C4 metabolic origin. No significant changes from rest 13CO2 enrichment were observed in tests with water and potato-derived glucose ingestion in subjects who excluded CHO of C4 metabolic origin from their diet.

Dynamic graciloplasty for treatment of faecal incontinence.

Serious faecal incontinence due to anal sphincter damage should be treated by surgery. Graciloplasty has had limited success because the gracilis is a fast-twitch muscle and fatigues quickly. A favourable outcome in a patient who had dynamic (electrically stimulated) graciloplasty encouraged us to further assess this procedure. Gracilis muscle transposition was done in ten patients with complete anal incontinence due to anal atresia, sphincter damage, or neurogenic causes, and who had had several other unsuccessful treatments. 6 weeks after muscle transposition, intramuscular leads were implanted and connected to an implantable electric stimulator. Eight patients became continent, one patient still has a diverting colostomy, and a fistula developed in the other patient. Anal sphincter pressure improved from 35 mm Hg without stimulation to 62 mm Hg with stimulation at 8 weeks (mean increase 28 mm Hg [95% confidence interval 18, 36], p less than 0.01). Retention time of a phosphate enema increased from 22 to 281 s (mean increase 259 s [82, 436], p less than 0.01). Defaecography showed that the new sphincter was functioning. Defaecation was possible when the stimulator was turned "off" with a magnet. Dynamic graciloplasty can restore continence and it improves quality of life in faecally incontinent patients for whom other treatments have been unsuccessful.

Carbohydrate supplementation, glycogen depletion, and amino acid metabolism during exercise.

Eight highly trained cyclists were studied during exercise after glycogen depletion (test A) and during carbohydrate (CHO) loading (test B). In test B subjects were able to complete 2 h of exercise at 70-75% maximal workload (Wmax), whereas the initial intensity of 70% Wmax had to be reduced to 50% in test A. Plasma ammonia increased more rapidly, and plasma alanine, glutamate, and glutamine were lower in test A. Exercise caused a 3.6-fold increase in the proportion of active branched-chain 2-oxoacid dehydrogenase (BC) complex in muscle in test A. No activation occurred in test B. There was an inverse correlation between the activity of the BC complex and the glycogen content of the postexercise biopsies. Exercise did not cause changes in the muscle content of ATP, ADP, AMP, IMP, hypoxanthine, and lactate. It is concluded that CHO loading abolishes increases in branched-chain amino acid (BCAA) oxidation during exercise and that part of the ammonia production during prolonged exercise originates from deamination of amino acids. The data appear to confirm the hypothesis (A.J. M. Wagenmakers, J.H. Coakley, and R.H.T. Edwards. Int. J. Sports Med. 11: S101-S113, 1990) that acceleration of the BCAA aminotransferase reaction may drain the tricarboxylic acid cycle and that glycogen is a carbon chain precursor of tricarboxylic acid cycle intermediates and glutamine.

Metabolism of branched-chain amino acids and ammonia during exercise: clues from McArdle's disease.

Patients with McArdle's disease (myophosphorylase deficiency) cannot use muscle glycogen as an energy source during exercise. They therefore are an ideal model to learn about the metabolic adaptations which develop during endurance exercise leading to glycogen depletion. This review summarizes the current knowledge of ammonia and amino acid metabolism in these patients and also adds several new data. During incremental exercise tests in patients with McArdle's disease, forearm venous plasma ammonia concentration rises to a value between 200 and 500 microM. Femoral arteriovenous difference studies show that muscle produces the ammonia. The leg release of both ammonia and glutamine (in mumol/min) has been estimated to be five- to tenfold larger in one of these patients than in healthy individuals exercising at comparable relative work load. Patients with McArdle's disease have a larger uptake of branched-chain amino acids (BCAA) by exercising leg muscles and show a more rapid activation of the muscle branched-chain 2-oxo acid dehydrogenase complex, a key enzyme in the degradation of the BCAA. In general, supplements of BCAA taken before the exercise test lead to a deterioration of exercise performance and a higher increase in heart rate and plasma ammonia during exercise, whereas supplements of branched-chain 2-oxo acids improve exercise performance and lead to a smaller increase in heart rate and plasma ammonia. At constant power output, patients with McArdle's disease show a rapid increase in heart rate and exertion perceived in the exercising muscles, which peak within 10 min after the start of exercise and then fall again ("second wind"). Peak heart rate and peak exertion coincide with a peak in plasma ammonia. Ammonia production during exercise in these patients is estimated to exceed the reported breakdown of ATP to IMP and therefore most likely originates from the metabolism of amino acids. Deamination of amino acids via the reactions of the purine nucleotide cycle and glutamate dehydrogenase are possible pathways. Deamination of glutamine, released by muscle, by glutaminase present in the endothelial cells of the vascular system may also contribute to the ammonia production. The observations made in these patients have led to the hypothesis that excessive acceleration of the metabolism of BCAA drains 2-oxoglutarate in the primary aminotransferase reaction and thus reduces flux in the citric acid cycle and impedes aerobic oxidation of glucose and fatty acids. This draining effect is normally counteracted by the anaplerotic conversion of muscle glycogen to citric acid cycle intermediates, a reaction which is severely hampered in these patients due to the glycogen breakdown defect.(ABSTRACT TRUNCATED AT 400 WORDS)