Acute depletion of plasma glutamine increases leucine oxidation in prednisone-treated humans

BACKGROUND, AIMS & METHODS: To determine whether depletion in plasma glutamine worsens the catabolic response to corticosteroids, seven healthy volunteers received oral prednisone for 6 days on two separate occasions, at least 2 weeks apart, and in random order. On the sixth day of each treatment course, they received 5 h intravenous infusions of L-[1-(14)C]-leucine and L-[1-(13)C]-glutamine in the postabsorptive state (1) under baseline conditions (prednisone only day) and (2) after 24h of treatment with phenylbutyrate (prednisone+phenylbutyrate day), a glutamine chelating agent. RESULTS: Phenylbutyrate treatment was associated with (1) an approximately 15% decline in plasma glutamine concentration (627+/-39 vs. 530+/-31 micromol l(-1); P<0.05), (2) no change in leucine appearance rate, an index of protein breakdown (124+/-9 vs. 128+/-9 micromol kg(-1) h(-1); NS) nor in non-oxidative leucine disposal, an index of whole body protein synthesis (94+/-9 vs. 91+/-7 micromol kg(-1) h(-1); NS), and (3) a approximately 25% rise in leucine oxidation (30+/-1 vs. 38+/-2 micromol kg(-1) h(-1), P<0.05), despite an approximately 25% decline (P<0.05) in leucine concentration. CONCLUSIONS: In a model of mild, stress-induced protein catabolism, depletion of plasma glutamine per se may worsen branched chain amino acid and protein wasting.     

Is glutamine a 'conditionally essential' amino acid in Duchenne muscular dystrophy?

To determine whether whole body protein kinetics are altered in Duchenne muscular dystrophy (DMD), six 9 +/- 1-year-old children with DMD and five weight and height matched controls, received intravenous infusion of L-[1-(13)C]leucine and L-[2-(15)N]glutamine in the post-absorptive state. Glutamine rate of appearance was approximatly 24% lower in DMD boys than in controls (321 +/- 22 vs 425 +/- 37 micromol kg(-1)h(-1), P< 0.05) resulting from a 32% decrease in glutamine de novo synthesis (230 +/- 21 vs 340 +/- 34 micromol kg(-1)h(-1), P< 0.05). Whereas there was no difference between groups in estimates of protein degradation and synthesis, leucine oxidation rate was 44% higher in DMD boys than in controls (23 +/- 2 vs 16 +/- 2 micromol kg(-1)h(-1), P< 0.05). The data suggest that the dramatic mucle mass loss observed in DMD boys is associated with a) significant protein wasting, since increased leucine oxidation reflects a more negative whole body leucine balance, and b) a significant decrease in glutamine availability in the postabsorptive state. Glutamine might therefore be a 'conditionally essential' amino-acid in DMD.     

Accelerated splanchnic amino acid uptake after cardiac surgery

Energy expenditure increases after cardiac surgery, but changes in peripheral tissue metabolism do not explain this increase. We hypothesized that the splanchnic region is a major contributor to the postoperative hypermetabolism, and this should be reflected in the exchange of amino acids across the splanchnic bed. We measured systemic and regional (splanchnic and leg) amino acid exchange, oxygen uptake and hemodynamics in 22 elective coronary bypass grafting patients postoperatively after arrival to the intensive care unit, 2 h later, and after stabilization of hemodynamics. Splanchnic uptake of glutamine (50 +/- 37 micromol/min/m2 to 78 +/- 37 micromol/min/m2, P < 0.05) and three of the gluconeogenetic amino acids, alanine (115 +/- 52 micromol/min/m2 to 183 +/- 70 micromol/min/m2, P < 0.05), serine (18 +/- 10 micromol/min/m2 to 26 +/- 13 micromol/min/m2) and threonine (20 +/- 8 micromol/min/m2 to 28 +/- 8 micromol/min/m2) increased during the observation period. Similarly, the oxygen consumption by the splanchnic region increased while splanchnic blood flow remained stable. A correlation between oxygen and amino acid uptake by the splanchnic bed was observed during the study period. Femoral exchange of glutamine and alanine did not change, although femoral blood flow and oxygen consumption increased during rewarming. High metabolic activity was observed in the splanchnic region during the early postoperative phase after hypothermic cardiac surgery. The increased plasma amino acid concentration indicates a release of amino acids from other sources than the peripheral muscle.     

Glucose kinetics and splanchnic uptake following mixed meal ingestion in cirrhotic-diabetic subjects

Although glucose intolerance and/or overt diabetes are common in cirrhotic subjects, the mechanism(s) that lead to post-prandial hyperglycemia in cirrhosis are not entirely known. To this aim, we measured whole-body rates of glucose appearance (Ra) and of disappearance (Rd) in cirrhotic-diabetic subjects and in controls, before and following a 4-hr administration of a mixed meal. In the post-prandial phase, endogenous and dietary glucose Ra, as well as first-pass splanchnic uptake of dietary glucose, were measured using a double (ie oral and intravenous) glucose tracer technique. In the fasting state, the cirrhotic patients were hyperglycemic (12.0 +/- 1.4 vs 4.4 +/- 0.2 mmol/l in controls, p < 0.001), had a higher glucose Ra (17.0 +/- 2.7 vs 10.2 +/- 0.5 micromol x kg(-1) x min(-1), p < 0.05) and a lower clearance rate (1.51 +/- 0.19 vs 2.32 +/- 0.06 ml x kg x min, p < 0.02). Following the meal, plasma glucose increased to greater values (p < 0.002) in the patients (to 16.8 +/- 2 mmol/l, mean values of the last 40 min) than in the controls (to 7.2 +/- 0.4 mmol/l). Insulin increased in both groups but it was 35% lower (p > 0.05) in the patients. Post-prandial total glucose Ra (cirrhotics: 21.3 +/- 2.6; controls: 19.2 +/- 1.4 pmol x kg(-1) x min(-1)), endogenous Ra (cirrhotics: 7.3 +/- 1.5; controls: 7.0 +/- 1.3 micromol x kg(-1) x min(-1)) and first-pass splanchnic uptake of dietary glucose (cirrhotics: 9.8 +/- 2.6; controls: 11.5 +/- 1.6 micromol x kg x min(-1)), were not different between the 2 groups, whereas glucose clearance remained lower (p<0.001) in the patients (1.31 +/- 0.25 ml x kg(-1) x min)-1)) than in the controls (2.72 +/- 0.26). These data demonstrate that, in cirrhotic-diabetic patients, post-pran-dial hyperglycemia is not due to a reduced extraction of dietary glucose nor to an increased endogenous production, but rather to a defect in peripheral glucose clearance, secondary to either insulin-resistance and/or relative insulin deficiency.     

Leucine kinetics at graded intakes in young men: quantitative fate of dietary leucine

To explore leucine metabolism in relation to leucine intake, five young adult men received an L-amino acid diet that supplied 40, 30, 20, and 10 mg leucine.kg-1.d-1 for 6 d. A stable-isotope-tracer infusion study was then conducted for 5 h while subjects received an intragastric infusion of the test diet. Primed, constant infusions of L-[1-13C]leucine (intragastric) and L-[2H3]leucine (intravenous) were given simultaneously. A final infusion study was conducted in subjects in the postabsorptive state after an additional 2 d with the 10-mg diet. Estimates were made of leucine flux and oxidation, rates of uptake and release of absorbed leucine by the splanchnic region, and leucine balance. The rate of appearance of dietary leucine in the systemic circulation (Leud) decreased (p less than 0.01) between the 40- and 10-mg diets. At the latter intake, splanchnic uptake was approximately 37% of absorbed leucine. The correlation between Leud and plasma leucine concentration was highly positive. A leucine intake of approximately 40 mg. kg-1.d-1 was close to that required to maintain leucine balance under these conditions.     

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.     

Effects of wine intake on postprandial plasma amino acid and protein kinetics in type 1 diabetes

BACKGROUND: Alcohol may impair protein turnover and insulin sensitivity in vivo. OBJECTIVE: The acute effects of moderate wine intake on amino acid kinetics and on the fractional synthetic rate (FSR) of albumin and fibrinogen in patients with type 1 diabetes were studied. DESIGN: Six patients with type 1 diabetes ingested an elementary mixed meal (46 kJ/kg) over 4 h, first without and 3 mo later with approximately 300 mL red wine. Postprandial glucose concentrations were maintained at <10 mmol/L. RESULTS: Postprandially, the FSR of fibrinogen was approximately 30% greater (21.5 +/- 6.6% compared with 14.1 +/- 3.6% of pool/d; P < 0.01) and glucagon concentrations were approximately 40% greater (103 +/- 20 compared with 61 +/- 13 ng/L; P < 0.015) with wine than without wine. However, the FSR of albumin and the rates of appearance of total and endogenous phenylalanine and leucine were not significantly different between treatments. First-pass splanchnic uptake (in micromol*kg(-1)*min(-1)) of dietary phenylalanine (0.22 +/- 0.02 compared with 0.19 +/- 0.02) and leucine (0.25 +/- 0.04 compared with 0.14 +/- 0.02) were greater with wine (P < 0.05), whereas dietary phenylalanine oxidation was lower with wine, by approximately 25% (0.10 +/- 0.02 compared with 0.14 +/- 0.01 micromol.kg(-1).min(-1); P < 0.05). Selected amino acid concentrations were significantly lower but glutamate concentrations were significantly higher with wine. CONCLUSIONS: In insulin-infused patients with type 1 diabetes, moderate wine intake with a meal resulted in 1) a higher fibrinogen FSR, glucagon concentration, and first-pass splanchnic uptake of leucine and phenylalanine; 2) lower dietary phenylalanine oxidation; 3) selective changes in plasma amino acid concentrations; 4) and no impairment in endogenous proteolysis and albumin synthesis.     

Aerobic exercise training decreases leucine oxidation at rest in healthy adults

Both exercise and dietary protein intake affect whole-body protein turnover (WBPTO). Few studies have investigated the effect of aerobic exercise training on WBPTO [leucine rate of appearance (Ra), oxidation (Ox), and nonoxidative leucine disposal (NOLD)] in untrained individuals consuming a specified level of protein. This study examined the effect of aerobic exercise training on WBPTO in untrained men and women during a controlled diet intervention providing 0.88 g protein/(kg . d). After a 2-wk adaptation to the study diet, 7 subjects [3 men, 4 women; 76.1 +/- 5.8 kg, 164.7 +/- 4.4 cm, 30.7 +/- 4.5% body fat, 39.1 +/- 2.8 VO(2max) (maximal oxygen uptake) mL/(kg . min)] participated in 4 wk of aerobic exercise training (running and walking 4-5 times/wk at 65-85% maximal heart rate). WBPTO (determined via constant infusion of 1-[(13)C] leucine), nitrogen balance, and body composition were determined at baseline and after 4 wk of training. Nitrogen balance (-1.0 +/- 0.7 vs. 0.9 +/- 1.1 g N/24 h, P = 0.03) improved with exercise training, whereas body mass and composition did not change. Leucine Ra did not change, Ox decreased [18 +/- 2 to 15 +/- 2 micromol/(kg . h), P 相似文献   

Mild-to-moderate chronic cholestatic liver disease increases leucine oxidation in children

Malnutrition is prevalent in children with chronic cholestatic liver disease. Using the noninvasive indicator amino acid oxidation (IAAO) technique, we recently determined that mild-to-moderate chronic cholestatic (MCC) liver disease increases the need for branched-chain amino acids (BCAA) in children. To examine the underlying mechanisms responsible for this increased need for BCAA in liver disease, we measured L-[1-(13C)]-leucine oxidation in the postabsorptive and fed states in 10 children with MCC liver disease (8.8 +/- 3.5 y) and in 11 healthy children (9.4 +/- 2.2 y). The oxidation of L-[1-(13C)]-leucine to 13CO2 [F13CO2 in micromol/(kg.h)] was determined after a primed, continuous oral administration of the tracer. Total BCAA in diet was provided at 300 mg/(kg.d) to ensure that leucine oxidation was measured when leucine intake was in excess of requirements. In the postabsorptive state, the rate of release of 13CO2 from 13C-leucine oxidation (F13CO2) and whole-body leucine oxidation were significantly higher in children with MCC liver disease (P < 0.05). However, F13CO2 and whole-body leucine oxidation did not differ in the fed state. We conclude that the increased need for dietary BCAA in MCC liver disease is mediated in part by increased leucine oxidation in the postabsorptive state.     

Oral glutamine and amino acid supplementation inhibit whole-body protein degradation in children with Duchenne muscular dystrophy

BACKGROUND: Glutamine has been shown to acutely decrease whole-body protein degradation in Duchenne muscular dystrophy (DMD). OBJECTIVE: To improve nutritional support in DMD, we tested whether oral supplementation with glutamine for 10 d decreased whole-body protein degradation significantly more than did an isonitrogenous amino acid control mixture. DESIGN: Twenty-six boys with DMD were included in this randomized, double-blind parallel study; they received an oral supplement of either glutamine (0.5 g . kg(-1) . d(-1)) or an isonitrogenous, nonspecific amino acid mixture (0.8 g . kg(-1) . d(-1)) for 10 d. The subjects in each group were not clinically different at entry. Leucine and glutamine metabolisms were estimated in the postabsorptive state by using a primed continuous intravenous infusion of [1-(13)C]leucine and [2-(15)N]glutamine before and 10 d after supplementation. RESULTS: A significant effect of time was observed on estimates of whole-body protein degradation. A significant (P < 0.05) decrease in the rate of leucine appearance (an index of whole-body protein degradation) was observed after both glutamine and isonitrogenous amino acid supplementation [x +/-SEM: 136 +/- 9 to 124 +/- 6 micromol . kg fat-free mass (FFM)(-1) . h(-1) for glutamine and 136 +/- 6 to 131 +/- 8 micromol . kg FFM(-1) . h(-1) for amino acids]. A significant (P < 0.05) decrease in endogenous glutamine due to protein breakdown was also observed (91 +/- 6 to 83 +/- 4 micromol . kg FFM(-1) . h(-1) for glutamine and 91 +/- 4 to 88 +/- 5 micromol . kg FFM(-1) . h(-1) for amino acids). The decrease in the estimates of whole-body protein degradation did not differ significantly between the 2 supplemental groups. CONCLUSION: Oral glutamine or amino acid supplementation over 10 d equally inhibits whole-body protein degradation in DMD.     

Leucine metabolism in preterm infants receiving parenteral nutrition with medium-chain compared with long-chain triacylglycerol emulsions

BACKGROUND: Although medium-chain triacylglycerols (MCTs) may be utilized more efficiently than long-chain triacylglycerols (LCTs), their effect on protein metabolism remains controversial. OBJECTIVE: The aim of the study was to compare the effects of mixed MCT-LCT and pure LCT emulsions on leucine metabolism in preterm infants. DESIGN: Fourteen preterm [gestational age: 30+/-1 wk; birth weight: 1409+/-78 g (x +/- SE)] neonates were randomly assigned to receive, from the first day of life, either a 50:50 MCT-LCT (mixed MCT group; n = 7) or an LCT (LCT group; n = 7) lipid emulsion as part of an isonitrogenous, isoenergetic total parenteral nutrition program. On the fourth day, infants received intravenous feeding providing 3 g lipid, 15 g glucose, and 3 g amino acids kg(-1) x d(-1) and underwent 1) indirect calorimetry and 2) a primed, 2-h infusion of H13CO3Na to assess the recovery of 13C in breath, immediately followed by 3) a 3-h infusion of L-[1-13C]leucine. RESULTS: The respiratory quotient tended to be slightly but not significantly higher in the mixed MCT than in the LCT group (0.96+/-0.06 compared with 0.93+/-0.03). We did not detect a significant difference between the mixed MCT and LCT groups with regard to release of leucine from protein breakdown (B; 309+/-40 compared with 257+/-46 micromol x kg(-1) x h(-1)) and nonoxidative leucine disposal (NOLD; 296+/-36 compared with 285+/-49 micromol x kg(-1) x h(-1)). In contrast, leucine oxidation was greater in the mixed MCT than in the LCT group (113+/-10 compared with 67+/-10 micromol x kg(-1) x h(-1); P = 0.007). Net leucine balance (NOLD - B) was less positive in the mixed MCT than in the LCT group (-14+/-9 compared with 28+/-10 micromol x kg(-1) x h(-1); P = 0.011). CONCLUSION: Mixed MCTs may not be as effective as LCT-containing emulsions in promoting protein accretion in parenterally fed preterm neonates.     

Net hepatic gluconeogenic amino acid uptake in response to peripheral versus portal amino acid infusion in conscious dogs

These studies were conducted to determine the effect of route of gluconeogenic amino acid delivery on the hepatic uptake of the amino acids. After a sampling period with no experimental intervention (basal period), conscious dogs deprived of food for 42 h received somatostatin, intraportal infusions of insulin (3-fold basal) and glucagon (basal), and a peripheral infusion of glucose to increase the hepatic glucose load 1.5-fold basal for 240 min. A mixture of alanine, glutamate, glutamine, glycine, serine and threonine was infused intraportally at 7.6 micromol. kg(-1). min(-1) (PorAA group, n = 6) or peripherally at 8.1 micromol. kg(-1). min(-1) (PerAA, n = 6), to match the hepatic load of gluconeogenic amino acids in PorAA. During the infusion period, there were no differences in PerAA and PorAA, respectively, with regard to arterial plasma insulin (144 +/- 18 and 162 +/- 18 pmol/L), glucagon (51 +/- 8 and 47 +/- 11 ng/L), hepatic glucose load (199.8 +/- 22.2 and 210.9 +/- 16.6 micromol. kg(-1). min(-1)), net hepatic glucose uptake (2.8 +/- 2.2 and 2.2 +/- 1.7 micromol. kg(-1). min(-1)), hepatic load of amino acids (68 +/- 14 and 62 +/- 7 micromol. kg(-1). min(-1)), or net hepatic glycogen synthesis (11.1 +/- 2.2 and 8.9 +/- 2.2 micromol. kg(-1). min(-1)). The net hepatic uptake of glutamine (2.1 +/- 0.4 vs. 0.8 +/- 0.3 micromol. kg(-1). min(-1)) and the net hepatic fractional extractions of glutamine (0.11 +/- 0.02 vs. 0.05 +/- 0.02) and serine (0.41 +/- 0.03 vs. 0.34 +/- 0.02) were greater in PorAA than in PerAA (P < 0.05). We speculate that one or more of the amino acids in the mixture causes enhancement of the net hepatic uptake and fractional extraction of glutamine, and perhaps other gluconeogenic amino acids, during intraportal amino acid delivery.     

Effect of zinc supplementation on protein metabolism in late-middle-aged men: The Zenith study

OBJECTIVE: Zinc (Zn) is an essential trace element that is a potent enhancer of protein metabolism due to its numerous roles in metabolic processes. Protein turnover decreases with age. We determined whether a Zn supplementation, which increases serum Zn concentration and Zn exchangeable pool mass, modifies whole-body protein turnover and albumin and fibrinogen synthesis rates in late-middle-aged men. METHODS: Three groups of 16 healthy subjects 55-70 y of age participated in a randomized, doubled-blinded, placebo-controlled intervention. Each group received 0, 15, or 30 mg/d of supplemental Zn for 6 mo. At the end of the supplementation period, each subject received an intravenous infusion of L-[1-13C] leucine to quantify whole-body leucine fluxes and synthesis rates of albumin and fibrinogen. RESULTS: In the placebo group, mean +/- SEM whole-body leucine fluxes to protein synthesis, to oxidation, and from protein degradation were 1.46 +/- 0.05, 0.40 +/- 0.01, and 1.73 +/- 0.06 micromol.kg(-1).min(-1), respectively. Zn supplementation did not significantly change whole-body leucine fluxes. In the placebo group, plasma concentration and fractional rate of protein synthesis were 45 +/- 1 g/L and 8.2 +/- 0.6%/d for albumin and 3.6 +/- 0.2 g/L and 16.7 +/- 1.3%/d for fibrinogen, respectively. Zn supplementation did not significantly change these parameters or the absolute rates of synthesis of these proteins. CONCLUSION: Increasing Zn supply does not modify whole-body protein metabolism and synthesis rates of albumin and fibrinogen in late-middle-aged men.     

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.     

Neither glutamine nor arginine supplementation of diets increase glutamine body stores in healthy growing rats

The aim of the work was to resolve whether glutamine and arginine supplemented diets affect plasma and tissue (muscle, liver and intestinal mucosa) glutamine concentrations, as well as glutaminase and glutamine synthetase specific activities. The trial was performed in growing rats fed 10% protein diets for 3 weeks. Protein sources were: whey proteins (W); whey proteins+free glutamine (WG); whey proteins+arginine (WA); and casein+wheat protein hydrolysate+acid whey (39:39:22), as source containing protein-bound glutamine (CGW). Rats fed the control diet (6.4% glutamine) (W) showed comparable glutamine body stores to those of rats fed the WG diet. In fact, glutamine sup- plementation down-regulated the hepatic glutamine synthetic capacity of growing rats (W/WG: 6.8+/-0.3 vs 6.0+/-0.2 nmol/min/mg protein). Arginine supplementation of the diet (up to 9% of the protein content) resulted in a decrease in plasma and tissue glutamine concentrations (W/WA: plasma, 1218+/-51 vs 1031+/-48 micromol/L; liver 7.5+/-0.4 vs 6.5+/-0.2 micromol/g; muscle: 5.7+/-0.2 vs 4.0+/-0.2 micromol/g). These data suggest that glutamine supplementation of the diet does not increase plasma and tissue glutamine concentrations in healthy growing rats, while the addition of arginine to the diet decreases glutamine body stores.     

Protein Redistribution From Skeletal Muscle to Splanchnic Tissue on Fasting and Refeeding in Young and Older Healthy Individuals

BackgroundDuring aging, a shift of protein metabolism from muscle to splanchnic tissue contributes to increased muscle protein loss after a period of metabolic stress (eg, fasting).ObjectiveTo study the adaptation of protein metabolism in the whole body and tissue (ie, skeletal muscle and splanchnic area) to metabolic stress, such as short-term fasting and refeeding, in aged people.Design and participantsWe studied splanchnic and muscle protein metabolism after 38 hours of fasting and refeeding in 7 young (5 men/2 women, 24.4 ± 2.0 years) and 8 elderly individuals (6 men/2 women, 70.6 ± 3.1 years).MeasurementsWe used intravenous (IV) L-[¹³C₆]phenylalanine, IV L-[²H₃]leucine, and oral L-[¹³C₁]leucine to obtain (1) whole-body protein kinetics, (2) muscle and albumin fractional synthesis rate (FSR, %/d; ¹³C₆-Phe, and ¹³C₁-Leu), and (3) splanchnic extraction during fasting and refeeding (%, ²H₃- and ¹³C₁-Leu).ResultsWhole-body protein breakdown was activated during fasting in young and older individuals (P < .01 vs fasted state). Muscle FSR remained unchanged in both groups and not stimulated by refeeding in either group with either IV ¹³C Phe or oral ¹³C Leu, probably because of high plasma levels of essential amino acids (EAAs) and branched-chain amino acids (BCAAs). Splanchnic extraction of leucine was 42% higher in the elderly individuals (P = .03 vs young) and was associated with an increased albumin synthesis rate in elderly individuals in the fed state (P < .05 vs young).ConclusionSplanchnic protein metabolism is modified by age, but this metabolic change is not associated with a lower synthesis rate of muscle protein, provided high plasma levels of essential EAAs are maintained. Our data also suggest that splanchnic protein synthesis is a metabolic priority during recovery after metabolic stress in healthy elderly persons and that it might be even more affected in polymedicated older individuals having chronic diseases.     

Decreased glutathione in patients with anorexia nervosa. Risk factor for toxic liver injury?

OBJECTIVE: To investigate glutathione and amino acids related to glutathione metabolism in patients with anorexia nervosa in order to test the hypothesis that these patients exhibit a deficiency of glutathione and therefore might be at an increased risk of developing toxic liver injury. DESIGN: Controlled observatory study and case report. SETTING: University Hospital. SUBJECTS: Subjects included 11 female patients with anorexia nervosa and 12 healthy female controls. INTERVENTIONS: Determination of fasting free and total glutathione, homocysteine, vitamins B(6) and B(12) and folic acid in plasma. RESULTS: A 14-y-old patient with a body mass index of 12.6 kg/m(2) presented with markedly elevated transaminases (ALAT >50 x upper limit of normal), and paracetamol was detected in her blood. Patients with anorexia nervosa exhibited lower circulating concentrations of free cysteine (8.9+/-1.5 vs 12.0+/-1.4 micromol/l) and free and total glutathione (5.0+/-1.3 vs 7.1+/-1.2 and 11.2+/-3.8 vs 16.2+/-5.0 micromol/l, respectively). The plasma concentrations of homocysteine (17.5+/-4.9 vs 12.0+/-3.8 micromol/l) and also of glycine (194+/-37 vs 143+/-41 micromol/l) and glutamine (422+/-51 vs 353+/-51 micromol/l) were significantly higher in patients with anorexia nervosa who were not deficient in folic acid, vitamin B(6) and B(12). CONCLUSIONS: Lower plasma concentrations of glutathione suggest lower intracellular concentrations of the tripeptide. Higher homocysteine, glycine and glutamine concentrations point to a decreased utilization of these amino acids for glutathione synthesis and an impairment of trans-sulfuration. Consequently, the capacity of patients with anorexia nervosa to detoxify electrophilic metabolites and reactive oxygen species via glutathione may be impaired.     

A tracer investigation of obligatory oxidative amino acid losses in healthy, young adults.

BACKGROUND: Estimation of the minimum requirement for indispensable amino acids (IAAs) has been attempted by assuming that obligatory oxidative losses (OOLs) of IAAs can be approximated from nitrogen losses and that the efficiency of utilization of IAAs at requirement intakes is approximately 70%. OBJECTIVE: We wished to determine the rates of OOLs in healthy adults, using L-[1-(13)C]leucine and L-[1-(13)C, methyl-(2)H(3)]methio-nine as tracers, after adjustment to a protein-free diet and how these rates compare with those when either sulfur amino acids (SAAs: methionine and cyst(e)ine) or leucine were removed from an otherwise adequate diet. DESIGN: Eleven subjects were randomly assigned to a 5-d protein-free diet or a 5-d diet providing adequate nitrogen and amino acids except for the SAAs or leucine. A 24-h constant intravenous infusion of [(15)N, (15)N]urea and L-[1-(13)C]leucine (Leu group; n = 5) or L-[1-(13)C, methyl-(2)H(3)]methionine (Met group; n = 6 ) began at 1800 on day 5 and rates of amino acid oxidation were determined. RESULTS: Mean (+/-SD) oxidation rates (mg kg(-)(1) d(-)(1)) of methionine and leucine were 6.4 +/- 1.4 and 24.7 +/- 3.6, respectively, with the protein-free diet; rates were significantly lower (3.9 +/- 2.2 and 7. 2 +/- 3.4, respectively) after the SAA- and leucine-free diets. Urea production was significantly lower (P < 0.01) with the protein-free than with the SAA- or leucine-free diet. CONCLUSIONS: Isotopically determined OOLs for methionine and leucine are consistent with losses predicted from nitrogen excretion, and consistent with our previous measurements of cysteine oxidation as an index of total SAA losses. The data further support our earlier conclusions regarding methionine sparing by cysteine and tentative recommended SAA requirements in adults.     

The route of administration (enteral or parenteral) affects the conversion of isotopically labeled L-[2-15N]glutamine into citrulline and arginine in humans

BACKGROUND: Glutamine exhibits numerous beneficial effects in experimental and clinical studies. It has been suggested that these effects may be partly mediated by the conversion of glutamine into citrulline and arginine. The intestinal metabolism of glutamine appears to be crucial in this pathway. The present study was designed to establish the effect of the feeding route, enteral or parenteral, on the conversion of exogenously administered glutamine into citrulline and arginine at an organ level in humans, with a focus on gut metabolism. METHODS: Sixteen patients undergoing upper gastrointestinal surgery received an IV or enteral (EN) infusion of L-[2-(15)N]glutamine. Blood was sampled from a radial artery and from the portal and right renal vein. Amino acid concentrations and enrichments were measured, and net fluxes of [(15)N]-labeled substrates across the portal drained viscera (PDV) and kidneys were calculated from arteriovenous differences and plasma flow. RESULTS: Arterial [(15)N]glutamine enrichments were significantly lower during enteral tracer infusion (tracer-to-tracee ratio [labeled vs unlabeled substrate, TTR%] IV: 6.66 +/- 0.35 vs EN: 3.04 +/- 0.45; p < .01), reflecting first-pass intestinal metabolism of glutamine during absorption. Compared with IV administration, enteral administration of the glutamine tracer resulted in a significantly higher intestinal fractional extraction of [(15)N]glutamine (IV: 0.15 +/- 0.03 vs EN: 0.44 +/- 0.08 micromol/kg/h; p < .01). Furthermore, enteral administration of the glutamine tracer resulted in higher arterial enrichments of [(15)N]citrulline (TTR% IV: 5.52 +/- 0.44 vs EN: 8.81 +/- 1.1; p = .02), and both routes of administration generated a significant enrichment of [(15)N]arginine (TTR% IV: 1.43 +/- 0.12 vs EN: 1.68 +/- 0.18). This was accompanied by intestinal release of [(15)N]citrulline across the PDV, which was higher with enteral glutamine (IV: 0.38 +/- 0.07 vs EN: 0.72 +/- 0.11 micromol/kg/h; p = .02), and subsequent [(15)N]arginine release in both groups. CONCLUSIONS: In humans, the gut preferably takes up enterally administered glutamine compared with intravenously provided glutamine. The route of administration, enteral or IV, affects the quantitative conversion of glutamine into citrulline and subsequent renal arginine synthesis in humans.     

Glutamine is an important precursor for de novo synthesis of arginine in humans

BACKGROUND: A metabolic relation exists between glutamine and arginine, 2 amino acids with properties that enhance the recovery of seriously ill patients. It is possible that glutamine exerts part of its beneficial effects by enhancing the availability of arginine. OBJECTIVES: We aimed to quantify under postabsorptive conditions the metabolic pathway of plasma glutamine into arginine via the intermediate citrulline and to establish the contribution of the kidneys to the synthesis of arginine. DESIGN: The study was conducted in patients during surgery. The metabolism of glutamine, citrulline, and arginine was studied by using intravenous administration of stable isotope tracers of the amino acids. Results were interpreted by using established equations. Parametric tests were used to test and correlate results. P < 0.05 was regarded as significant. RESULTS: Mean (+/-SE) whole-body plasma turnover rates of glutamine, citrulline, and arginine were 240 +/- 14, 6.2 +/- 0.6, and 42 +/- 2.9 micromol x kg(-1) x h(-1), respectively (P < 0.01). Plasma turnover of citrulline derived from glutamine was shown to be 5.1 +/- 0.7 micromol x kg(-1) x h(-1), and arginine derived from citrulline was shown to be 4.9 +/- 0.9 micromol x kg(-1) x h(-1) (P < 0.01). The contribution of plasma glutamine to plasma arginine derived from plasma citrulline was calculated to be 64%. The kidneys were observed to take up >50% of circulating plasma citrulline and to release equimolar amounts of arginine into plasma. CONCLUSIONS: This study shows that glutamine is an important precursor for the synthesis of arginine in humans. It also provides a firm basis for future studies exploring the effect of a treatment dose and the route of administration (enteral or parenteral) of glutamine.