L-glutamine-enriched parenteral nutrition in catabolic patients.
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Journal Article↗
Biomedical subjects
T R Ziegler
Publications and source records attributed to T R Ziegler.
Anabolic therapy with growth hormone accelerates protein gain in surgical patients requiring nutritional rehabilitation.
OBJECTIVE: The authors investigated the effects of exogenous growth hormone (GH) on protein accretion and the composition of weight gain in a group of stable, nutritionally compromised postoperative patients receiving standard hypercaloric nutritional therapy. SUMMARY BACKGROUND DATA: A significant loss of body protein impairs normal physiologic functions and is associated with increased postoperative complications and prolonged hospitalization. Previous studies have demonstrated that standard methods of nutritional support enhance the deposition of fat and extracellular water but are ineffective in repleting body protein. METHODS: Fourteen patients requiring long-term nutritional support for severe gastrointestinal dysfunction received standard nutritional therapy (STD) providing approximately 50 kcal/kg/day and 2 g of protein/kg/day during an initial 7-day equilibrium period. The patients then continued on STD (n = 4) or, in addition, received GH 0.14 mg/kg/day (n = 10). On day 7 of the equilibrium period and again after 3 weeks of treatment, the components of body weight were determined; these included body fat, mineral content, lean (nonfat and nonmineral-containing tissue) mass, total body water, extracellular water (ECW), and body protein. Daily and cumulative nutrient balance and substrate oxidation studies determined the distribution, efficiency, and utilization of calories for protein, fat, and carbohydrate deposition. RESULTS: The GH-treated patients gained minimal body fat but had significantly more lean mass (4.311 +/- 0.6 kg vs. 1.988 +/- 0.2 kg, p < or = 0.03) and more protein (1.417 +/- 0.3 kg vs. 0.086 +/- 0.1 kg, p < or = 0.03) than did the STD-treated patients. The increase in lean mass was not associated with an inappropriate expansion of ECW. In contrast, patients receiving STD therapy tended to deposit a greater proportion of body weight as ECW and significantly more fat than did GH-treated patients (1.004 +/- 0.3 kg vs. 0.129 +/- 0.2 kg, p < 0.05). GH administration altered substrate oxidation (respiratory quotient = 0.94 +/- 0.02 GH vs. 1.17 +/- 0.05 STD, p < or = 0.0002) and the use of available energy, resulting in a 66% increase in the efficiency of protein deposition (13.37 +/- 0.8 g/1000 kcal vs. 8.04 g +/- 3.06 g/1000 kcal, p < or = 0.04). CONCLUSIONS: GH administration accelerated protein gain in stable adult patients receiving aggressive nutritional therapy without a significant increase in body fat or a disproportionate expansion of ECW. GH therapy accelerated nutritional repletion and, therefore, may shorten the convalescence of the malnourished patient requiring a major surgical procedure.
Adult↗
Clinical and metabolic efficacy of glutamine-supplemented parenteral nutrition after bone marrow transplantation. A randomized, double-blind, controlled study.
OBJECTIVE: To determine whether glutamine-supplemented parenteral nutrition improves nitrogen retention and reduces hospital morbidity compared with standard parenteral nutrition after bone marrow transplantation. DESIGN: Double-blind, randomized, controlled clinical trial. SETTING: University teaching hospital. PATIENTS: Forty-five adults receiving allogeneic bone marrow transplants for hematologic malignancies. INTERVENTION: Parenteral nutrition was initiated the day after bone marrow transplantation (day 1). The experimental solution was supplemented with L-glutamine (0.57 g/kg body weight per day) and provided estimated requirements for energy and protein. The control solution was a standard, glutamine-free, isonitrogenous, isocaloric formula. MEASUREMENTS: Nitrogen balance was determined between days 4 and 11 in the initial 23 patients. The incidence of clinical infection and microbial colonization, time until bone marrow engraftment, indices of clinical care, and other data related to hospital morbidity were recorded for all patients. RESULTS: The glutamine-supplemented patients (n = 24) were clinically similar to the controls (n = 21) at entry. Nutrient intake was similar in both groups; however, nitrogen balance was improved in the glutamine-supplemented patients relative to the controls (-1.4 +/- 0.5 g/d compared with -4.2 +/- 1.2; P = 0.002). Fewer experimental patients developed clinical infection (three compared with nine in the control group; P = 0.041), and the incidence of microbial colonization was also significantly reduced. Hospital stay was shortened in patients receiving glutamine supplementation (29 +/- 1 d compared with 36 +/- 2 d; P = 0.017). CONCLUSION: Patients receiving glutamine-supplemented parenteral nutrition after bone marrow transplantation had improved nitrogen balance, a diminished incidence of clinical infection, lower rates of microbial colonization, and shortened hospital stay compared with patients receiving standard parenteral nutrition. These effects occurred despite no differences between groups in the incidence of fever, antibiotic requirements, or time to neutrophil engraftment.
Adult↗
Recombinant human growth hormone enhances the metabolic efficacy of parenteral nutrition: a double-blind, randomized controlled study.
This multicenter, randomized, double-blind study was performed to investigate whether recombinant GH improves the efficacy of total parenteral nutrition (TPN). Fifteen stable patients requiring parenteral feeding due to gastrointestinal/pancreatic disease were studied. Constant maintenance TPN providing approximately 30 kcal/kg day and approximately 1.6 g protein/kg.day was administered during an initial 7-day baseline period. After randomization, daily sc injections of saline (control, n = 9) or GH (10 mg/day, n = 6) were administered a 14-day treatment period as nutrient intake remained constant. Elemental balances for nitrogen (N), potassium (K), phosphorus (P), and sodium (Na) were determined daily and serial blood indices, vital signs, and other clinical parameters were monitored. Nutrient balances approached equilibrium during the baseline week in both groups. With GH administration, a significant increase in N, K, and P balance occurred; in contrast, nutrient balances did not change significantly from baseline values in control patients. The cumulative change (delta) in nutrient balances from the baseline week was also significantly greater in the GH-treated patients (delta N: control+2 +/- 7 g vs. GH+36 +/- 6. g, P less than 0.005; delta K:+57 +/- 45 mmol vs.+199 +/- 19 mmol, P less than 0.03; delta P: -27 +/- 30 mmol vs. +91 +/- 69 mmol, P less than 0.02). Plasma insulin-like growth factor-I concentrations rose 5-fold and serum cholesterol rose slightly with GH; no other significant change in group mean blood values occurred. One patient receiving GH and chronic prednisone therapy developed moderate hyperglycemia and mild peripheral edema; no other deleterious effects attributable to GH were observed. GH was well tolerated and significantly enhanced nutrient retention compared to standard parenteral feeding alone. GH improves the efficacy of parenteral nutrient utilization in patients requiring TPN.
Adolescent↗
Insulin-like growth factor-I response is comparable following intravenous and subcutaneous administration of growth hormone.
Subcutaneous (sq) administration of recombinant human growth hormone (r-hgh) has an anabolic effect and increases systemic insulin-like growth factor (IGF-I) in surgical patients. IGF-I is a mediator of growth hormone (gh) anabolic effects. To determine the effect of intravenous (iv) administration of r-hgh on systemic IGF-I, 11 patients were given 14 1-week courses of daily 8-hr infusions of r-hgh (10 mg in 500 ml D5W). Serum gh and IGF-I levels were measured. To compare routes of administration, iv r-hgh patients were matched to comparable sq r-hgh patients and IGF-I responses were examined. Illness severity effect on IGF-I response to r-hgh was assessed by dividing 16 burn patients who received either iv or sq r-hgh into two groups on the basis of severity scores. Analysis of the data showed that IGF-I levels increased significantly after iv r-hgh, IGF-I response to iv r-hgh (1.14 +/- 0.18 U/ml to 4.12 +/- 0.65 U/ml) was not different from IGF-I response to sq r-hgh (1.04 +/- 0.36 U/ml to 4.96 +/- 1.09 U/ml). Increasing illness severity attenuated the IGF-I response in the more severely injured group (0.91 +/- 17 U/ml to 2.40 +/- 0.38 U/ml) relative to the less severely injured group (1.37 +/- 0.22 U/ml to 5.53 +/- 0.78 U/ml) despite a significant increase in IGF-I after gh in both groups. In summary, IGF-I increased significantly after iv r-hgh and the increases were similar to those seen after sq r-hgh in comparable patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Glutamine-enriched intravenous feedings attenuate extracellular fluid expansion after a standard stress.
A double-blind, randomized controlled trial was performed to determine the effect of glutamine (GLN)-enriched intravenous feedings on the volume and distribution of body fluids in catabolic patients. Subjects with hematologic malignancies in remission underwent a standard treatment of high-dose chemotherapy and total body irradiation before bone marrow transplantation. After completion of this regimen, they were randomized to receive either standard parenteral nutrition (STD, n = 10) or an isocaloric, isonitrogenous nutrient solution enriched with crystalline L-glutamine (0.57 g/kg/day, GLN, n = 10). Extracellular water (ECW) and total body water (TBW), determined by bromide and heavy water dilution techniques, were measured before the conditioning treatment and after termination of the intravenous feedings that were administered for 27 +/- 1 days. In addition electrical resistance (R, in ohms, omega) and reactance (Xc, omega) of the body to a weak alternating current were measured at these time points. Both study groups were comparable for age, weight, height, sex, and diagnosis. Initial TBW was highly related to electrical resistance (r = -0.93, p less than 0.001). After conditioning therapy, bone marrow infusion, and intravenous feedings, a 20% expansion in ECW was observed in the STD group (ECW: 18.0 +/- 1.1 L vs. 14.9 +/- 1.0, p = 0.012), and this fluid retention was associated with a marked decrease in electrical resistance (R: 514 +/- 28 omega vs. 558 +/- 26, p less than 0.05). In contrast the extracellular fluid compartment in patients receiving GLN-supplementation did not change (ECW: 15.8 +/- 0.9 L vs. 15.4 +/- 0.8, p = 0.49), and the body's resistance was maintained (R: 552 +/- 27 omega vs. 565 +/- 23, p = 0.42). Expansion of ECW could not be related to differences in fluid or sodium intake, or to the use of diuretics or steroids. Patients receiving the STD solution, however, exhibited a greater number of positive microbial cultures (p less than 0.01) and a higher rate of clinical infection compared with the GLN patients (5/10 vs. 0/10, p less than 0.05); the fluid expansion in infected STD patients was greater compared with uninfected individuals (delta ECW: + 5.0 +/- 1.4 vs. 0.7 +/- 0.5, p = 0.007). In this model of catabolic stress, fluid retention and expansion of the extracellular fluid compartment commonly observed after standard total parenteral nutrition can be attenuated by administering glutamine-supplemented intravenous feedings, possibly by protecting the host from microbial invasion and associated infection.
Adult↗
Effects of growth hormone administration on dehydroepiandrosterone sulphate, androstenedione, testosterone and cortisol metabolism during nutritional repletion.
This study evaluated whether pharmacological doses of recombinant human growth hormone (hGH) influences androgen or cortisol metabolism during nutritional repletion following prolonged illness. Stable hospitalized adults (three males, seven female) receiving constant calorie and protein intake were studied. An initial control week was followed by a treatment period during which hGH (10 mg/day s.c.) was administered daily. Prior to hGH treatment, serum and 24-h urinary concentrations of dehydroepiandrosterone sulphate (DS) were below the normal range; serum androstenedione and testosterone concentrations were within the lower limit of normal. In contrast, serum cortisol (F) and 24-h urinary F excretion were normal. During hGH treatment, nitrogen balance became positive and plasma insulin-like growth factor I (IGF-I) concentrations rose five to seven-fold. However, serum DS, androstenedione, testosterone and F, and urinary F excretion did not change, while 24-h urinary DS excretion fell significantly. Growth hormone administration markedly stimulated protein anabolism but did not increase the low concentrations of circulating androgens or alter the disassociation between adrenal androgen and F release in stable hospitalized males and females. Thus, hGH does not appear to function as a cortical adrenal androgen stimulating hormone (CASH) or regulate adrenal cortisol or gonadal androgen release in this clinical setting.
Adrenal Cortex↗
Effects of recombinant human growth hormone in adults receiving maintenance hemodialysis.
Administration of recombinant human growth hormone stimulates protein synthesis, decreases urea generation, and improves nitrogen balance in individuals with normal renal function. However, little information is available concerning the effects of growth hormone in patients with renal disease. This pilot study evaluated urea kinetics and clinical/metabolic responses to short-term growth hormone administration in five clinically stable adult patients requiring maintenance hemodialysis for end-stage renal failure. The dialysis prescription, medications, and oral calorie and protein intake of each patient remained constant during an initial control week and a subsequent 2-wk growth hormone treatment period. During treatment, growth hormone (5 or 10 mg) was administered s.c. immediately after each dialysis session. Protein and calorie intake, vital signs, body weight, and other clinical parameters remained stable throughout the 3-wk study. BUN values fell significantly (approximately 20 to 25%) during growth hormone administration compared with control week values. Similarly, urea kinetic modeling demonstrated a significant reduction in urea generation and the protein catabolic rate during each week of growth hormone treatment. Plasma insulin-like growth factor I levels rose significantly, and serum phosphorus and intact parathyroid hormone levels fell significantly during growth hormone administration. Serum glucose and other blood values remained stable. This preliminary study suggests that growth hormone administration reduces urea generation and improves the efficiency of dietary protein utilization in stable adult hemodialysis patients. Growth hormone may be a useful adjunctive therapy to diminish body protein catabolism in this patient population.
Adult↗
Safety of glutamine-enriched parenteral nutrient solutions in humans.
To determine the safety of glutamine-enriched parenteral nutrition, seven normal volunteers were admitted to the Clinical Research Center for three 5-d study periods. The subjects received infusions of parenteral nutrients containing increasing doses of glutamine (0, 0.285, and 0.570 g.kg body wt-1.d-1) substituted for alanine and glycine. Each study period was preceded by greater than or equal to 2 wk of normal food intake. The diets were isocaloric (1.2X estimated basal metabolic rate) and isonitrogenous (1.5 g protein.kg-1.d-1) with nonprotein calories given as dextrose (38%) and fat emulsion (62%). The diets were all well tolerated and there were no untoward effects. Plasma glutamine concentrations increased significantly with glutamine administration but plateaued at concentrations approximately 25% above control values. Ammonia and glutamate, potentially toxic metabolites of glutamine, did not change significantly with glutamine enrichment. Nitrogen balance and hormonal concentrations were unchanged during the three dietary periods. Results of mental-status examinations and continuous performance testing were normal and unchanged throughout the three periods. Glutamine-enriched parenteral nutrient solutions are well tolerated with no associated signs of toxicity in normal humans.
Adult↗
Increased intestinal permeability associated with infection in burn patients.
Thermal injury may be associated with disruption of normal gut barrier integrity. To test this hypothesis, we assessed intestinal permeability with the nonmetabolizable, poorly absorbed disaccharide lactulose, which is efficiently excluded by the normal intestinal mucosa. Permeability studies were performed in 15 burned patients (aged 18 to 67 years; mean burn size, 40%) and 11 healthy controls. Lactulose, 10 g, was administered enterally, together with 5 g of mannitol as a control, and urinary excretion rates were determined. Lactulose excretion and the lactulose/mannitol excretion ratio increased threefold (160 +/- 30 vs 57 +/- 7 mumol and 0.113 +/- 0.033 vs 0.035 +/- 0.005) in the infected patients (sepsis score, 10 +/- 2; burn size, 38% +/- 6%). In contrast, noninfected burn patients (sepsis score, 0) had permeability values similar to those of controls (66 +/- 10 mumol and 0.036 +/- 0.007). Permeability increased as the severity of infection increased. Infection in burn patients is associated with increased bowel permeability. The intestine may be a primary source of sepsis. Alternatively, the systemic response to infection may alter gut barrier function, which could facilitate translocation of bacteria and absorption of endotoxin.
Adolescent↗
A single dose of endotoxin increases intestinal permeability in healthy humans.
To investigate the effects of endotoxin on gut barrier function, we performed paired studies of intestinal permeability in healthy humans (N = 12) receiving intravenous Escherichia coli endotoxin (4 ng/kg) or 0.9% saline solution. Two nonmetabolizable sugars, lactulose and mannitol, which are standard permeability markers, were administered orally, 30 minutes before and 120 minutes after the test injection. The 12-hour urinary excretion of these substances after endotoxin/saline solution administration was used to quantitate intestinal permeability. After endotoxin administration systemic absorption and excretion of lactulose increased almost two-fold (mean +/- SEM, 263 +/- 36 mumol per 12 hours vs 145 +/- 19 mumol per 12 hours during saline studies). Similar but less marked alterations in mannitol absorption and excretion occurred after endotoxin injection (5.7 +/- 0.3 mmol per 12 hours vs 4.9 +/- 0.3 mmol per 12 hours). When individual 12-hour lactulose excretion after endotoxin administration was related to the magnitude of systemic responses, a significant relationship occurred between lactulose excretion and elaboration of norepinephrine and between lactulose excretion and minimum white blood cell count. These data suggest that a brief exposure to circulating endotoxin increases the permeability of the normal gut. These observations are consistent with the hypothesis that during critical illness, prolonged or repeated exposure to systemic endotoxins or associated cytokines may significantly compromise the integrity of the gastrointestinal mucosal barrier.
Administration, Oral↗
Metabolic effects of recombinant human growth hormone in patients receiving parenteral nutrition.
Recombinant human methionyl growth hormone (Protropin) (Genetech, Inc., San Francisco, CA) administered to normal volunteers receiving hypocaloric parenteral nutrition minimized weight loss and induced positive nitrogen balance. To evaluate whether growth hormone (GH) can promote anabolism in surgical patients, 11 stable malnourished individuals were studied. In the initial trial, subjects received a constant parenteral infusion of a hypocaloric diet that provided approximately 1100 kcal/24 hr and 1.3 g protein/kg/24 hr for at least 2 weeks. During 1 week, GH 10 mg was given subcutaneously daily, whereas the other week served as the control. Daily balance studies demonstrated that administration of GH resulted in significant retention of nitrogen (+3.4 g/24 h) and phosphorus (+218 mg/24 h), despite provision of only 60% of caloric requirements. With GH, serum blood urea nitrogen (BUN) and potassium fell, whereas glucose and insulin tended to rise, and levels of insulin-like growth factor 1 increased three to fourfold. Weight gain occurred with GH and was associated with positive mineral and water balance. Six patients received GH (10 mg subcutaneously daily) for 13-25 consecutive days after an initial control week. Significant nitrogen and phosphorus retention occurred over the entire period of GH administration, and no significant side effects were observed. In these depleted patients, GH caused significant and sustained nitrogen retention over a wide range of nutritional support. GH appears to enhance the efficacy of parenteral nutrition in stable individuals requiring repletion of body protein.
Adult↗
The gut: a central organ after surgical stress.
The intestinal tract plays a central role in the protein catabolic response after injury and infection. The mucosa utilizes glutamine and thus spares glucose--presumably sparing this essential fuel source for tissues with an obligate glucose requirement. With inadequate nutritional support or prolonged stress, glutamine levels decrease in both the plasma and the tissue pools, which suggests that glutamine deficiency occurs. This is associated in time with atrophy of the gastrointestinal mucosa. This provision of dietary glutamine results in correction of the abnormally low glutamine concentrations and increased cellularity of the gut mucosa. The derangements in the intestinal mucosa associated with starvation, injury, infection, immunosuppression, chemotherapy, lack of enteral feedings, and other stresses are associated with a breakdown in the barrier function of the gut. Both bacteria and their toxins may enter the host from the intestinal lumen. Through interaction with the reticuloendothelial system, cytokines are produced, which stimulate the pituitary-adrenal axis and thus contribute to the stress response. The elaboration of glucocorticoids facilitates proteolysis, thus increasing glutamine release from skeletal muscle for gut repair. Although this homeostatic mechanism appears to aid mucosal repair and support immunologic responses, severe injury or prolonged glutamine deficits do not adequately support intestinal recovery and allow this cycle to become self-perpetuating (Fig 3). Adequate enteral feedings initiated early in the course of a disease appear to maintain adequate gut barrier function. In the frequent circumstance when feeding by this route is inadequate or impossible, glutamine-containing parenteral feedings offer an appropriate alternative therapy for bowel and immunologic support. Glutamine-containing parenteral feedings are associated with increased mucosal cellularity and improved survival after gut injury. Specific hormones also stimulate mucosal growth, and it is anticipated that a combination of hormones and specific nutrients will provide optimal support of the gut mucosa in the severely ill patient.
Animals↗
Glutamine: from basic science to clinical applications.
Glutamine (Gln) has been one of the most intensively studied nutrients in the field of nutrition support in recent years. Interest in provision of Gln derives from animal studies in models of catabolic stress, primarily in rats. Enteral or parenteral Gln supplementation improved organ function and/or survival in most of these investigations. These studies have also supported the concept that Gln is a critical nutrient for the gut mucosa and immune cells. Recent molecular and protein chemistry studies are beginning to define the basic mechanism involved in Gln action in the gut, liver and other cells and organs. Double-blind prospective clinical investigations to date suggest that Gln-enriched parenteral or enteral feedings are generally safe and effective in catabolic patients. Intravenous Gln (either as the L-amino acid or as Gln-dipeptides) has been shown to increase plasma Gln levels, exert protein anabolic effects, improve gut structure and/or function and reduce important indices of morbidity, including infection rates and length of hospital stay in selected patients subgroups. Additional blinded studies of Gln administration in catabolic patients and increasing clinical experience with Gln-enriched nutrient products will determine whether routine Gln supplementation should be given in nutrition support, and to whom. Taken together, the data obtained over the past decade or so of intensive research on Gln nutrition demonstrate that this amino acid is an important dietary nutrient and is probably conditionally essential in humans in certain catabolic conditions.
Animals↗
Keratinocyte growth factor enhances early gut adaptation in a rat model of short bowel syndrome.
OBJECTIVE: To evaluate the effects of keratinocyte growth factor (KGF) on intestinal adaptation after resection of 85% of the small intestine and consider its potential application in short bowel syndrome (SBS). STUDY DESIGN: Experimental study using a known model of SBS. ANIMAL POPULATION: Thirty male Sprague Dawley rats. METHODS: Four groups of animals were designated. Two groups underwent 85% resection of the small intestine, while the other two groups were sham-operated, undergoing transection and reanastomosis. Resected and sham-operated groups then received either 3 mg/kg KGF or vehicle subcutaneously daily for 3 days. Gut adaptation was evaluated by measurements of mucosal cellularity and biochemical activity in duodenal, jejunal, and ileal segments. RESULTS: Significant small intestinal growth after bowel resection alone was confirmed in resected versus sham-operated rats. KGF further augmented this growth in the resected animals. Mucosal wet weight of the small intestine increased with resection and was further increased (by 20% or more) with KGF administration. Mucosal thickness, villus length, and crypt depth exhibited similar patterns of response. The KGF-induced increase in mucosal morphology was accompanied by increased mucosal DNA and protein content, followed by a trend toward increased mucosal enzyme activity. Histology demonstrated an increase in goblet cells in KGF-treated animals. In situ hybridization analysis demonstrated that KGF markedly increased mucosal expression of intestinal trefoil protein (ITF) mRNA. CONCLUSIONS: KGF enhances gut growth, differentiation, and gene regulation during adaptation in rat small intestine after massive resection. CLINICAL RELEVANCE: KGF may be beneficial in the management of veterinary and human patients undergoing massive intestinal resection.
Adaptation, Physiological↗
Enteral nutrition and keratinocyte growth factor regulate expression of glutathione-related enzyme messenger RNAs in rat intestine.
BACKGROUND: Malnutrition is associated with increased reactive oxygen species (ROS) formation and depletion of the critical antioxidant glutathione (GSH) in the intestine. The malnutrition-induced decrease in gut GSH levels is prevented by recombinant keratinocyte growth factor (KGF) administration. We investigated whether enzymes that are induced by oxidants and modulate tissue GSH supply are regulated by enteral nutrients or KGF at the messenger RNA (mRNA) level. METHODS: Adult rats were fasted for 3 days alone or fasted for 3 days then refed ad libitum. In a second model, rats were fasted for 3 days and then refed ad libitum or 25% of ad libitum intake with daily intraperitoneal saline or recombinant KGF (5 mg/kg/d) for 3 subsequent days. mRNA levels for gamma-glutamylcysteine synthetase (gamma-GCS), gamma-glutamyl transpeptidase (gamma-GT), glutathione-S-transferase Ya-subunit, gastrointestinal glutathione peroxidase (GI-GPx), and non-selenium-dependent glutathione peroxidase (ns-GPx) were determined in ileum and colon by ribonuclease protection assay. RESULTS: Fasting increased ileal gamma-GCS, ns-GPx, and glutathione-S-transferase mRNAs (by 36%, 165%, and 130% of controls) and decreased GI-GPx mRNA (to 55% of controls). In the colon, mRNAs for GSH-related enzymes were unchanged by fasting or refeeding. Prolonged enteral nutrient restriction (25% refeeding after a 3-day fast) increased gamma-GCS and glutathione-S-transferase mRNAs (by >270% of controls), decreased GI-GPx mRNA (to <50% of controls) in ileum and colon and increased ns-GPx mRNA (by 180%) in colon. KGF treatment increased ns-GPx mRNA in the ileum and colon and glutathione-S-transferase mRNA in the colon (by >200% of controls). CONCLUSIONS: Enteral nutrient intake regulates GSH-related enzyme mRNA levels in the intestine, which may contribute to the decrease in mucosal GSH during malnutrition. Increased ns-GPx and glutathione-S-transferase mRNA levels during malnutrition and with KGF administration may increase detoxifying functions in the gut under these conditions.
Analysis of Variance↗
Growth factors regulation of rabbit sodium-dependent neutral amino acid transporter ATB0 and oligopeptide transporter 1 mRNAs expression after enteretomy.
BACKGROUND: Sucessful intestinal adaptation after massive enterectomy is dependent on increased efficiency of nutrient transport. However, midgut resection (MGR) in rabbits induces an initial decrease in sodium-dependent brush border neutral amino acid transport, whereas parenteral epidermal growth factor (EGF) and growth hormone (GH) reverse this downregulation. We investigated intestinal amino acid transporter B0 (ATB0) and oligopeptide transporter 1 (PEPT 1) mRNA expression after resection and in response to EGF and/or GH. METHODS: Rabbits underwent anesthesia alone (control) or proximal, midgut, and distal resections. Full-thickness intestine was harvested from all groups on postoperative day (POD) 7, and on POD 14 from control and MGR rabbits. A second group of MGR rabbits received EGF and/or GH for 7 days, beginning 7 days after resection. ATB0 and PEPT 1 mRNA levels were determined by Northern blot analysis. RESULTS: In control animals, ileal ATB0 mRNA abundance was three times higher than jejunal mRNA, whereas PEPT 1 mRNA expression was similar. By 7 and 14 days after MGR, jejunal ATB0 mRNA abundance was decreased by 50% vs control jejunum. A 50% decrease in jejunal PEPT 1 message was delayed until 14 days after MGR. Treatment with EGF plus GH did not alter ATB0 mRNA expression but doubled PEPT 1 mRNA in the jejunum. CONCLUSION: The site of resection, time postresection, and growth factors treatment differentially influence ATB0 and PEPT 1 mRNA expression. Enhanced sodium-dependent brush border neutral amino acid transport with GH plus EGF administration is independent of increased ATB0 mRNA expression in rabbit small intestine after enterectomy.
Adaptation, Physiological↗
Safety and metabolic effects of L-glutamine administration in humans.
A series of dose-response studies was conducted to evaluate the clinical safety, pharmacokinetics, and metabolic effects of L-glutamine administered to humans. Initial studies in normal individuals evaluated the short-term response to oral loads of glutamine at doses of 0, 0.1, and 0.3 g/kg. A dose-related increase in blood glutamine occurred after oral loading and elevation of amino acids known to be end products of glutamine metabolism occurred (including alanine, citrulline, and arginine). No evidence of clinical toxicity or generation of toxic metabolites (ammonia and glutamate) was observed. Glutamine was infused intravenously in normal subjects over 4 hr at doses of 0.0125 and 0.025 g/kg/hr. In addition, glutamine was evaluated as a component of parenteral nutrition solutions (0.285 and 0.570 g/kg/day) administered for 5 days to normal subjects. Intravenous administration of glutamine was well tolerated without untoward clinical or biochemical effects. Subsequent studies in patients receiving glutamine-enriched parenteral nutrition for several weeks confirmed the clinical safety of this approach in a catabolic patient population. In addition, nitrogen retention appeared to be enhanced when glutamine was administered at a dose of 0.570 g/kg/day in a balanced nutritional solution providing adequate calories (145% of basal) and protein (1.5 g/kg/day). Nitrogen balance in patients receiving lower doses of glutamine (0.285 g/kg/day) was similar to that in patients receiving standard formulations. Further controlled clinical trials of the metabolic efficacy, tolerance, and dose response of glutamine in other patient groups are necessary to determine the appropriate use of glutamine enrichment of nutrient solutions.
Administration, Oral↗