Search

Summary The value of transthyretin (TTR) measurement for assessing malnutrition is under debate due to its sensitivity to inflammation and frequent confusion over its meaning (i.e. as a marker of diagnosis, prognosis, or efficacy of refeeding). Moreover, there is still no ESPEN/ASPEN guideline on its use and cut-off values. Here the aim was to evaluate the overall perception of the value of this parameter and its utilization worldwide. A panel of international experts in the field were surveyed on the use of TTR in clinical practice in their country, on the guidelines issued by their national health authorities, and on the cut-off values used to diagnose malnutrition. A total of 31 experts (nutrition [n = 9], surgery [n = 8], critical care [n = 4], geriatrics [n = 4], biology [n = 3], pediatrics [n = 1], internal medicine [n = 1] and gastroenterology [n = 1]) from 16 countries participated. TTR only appears in Italian, Polish, British and French national guidelines giving cut-off values for mild/moderate/severe malnutrition. TTR is frequently used in research yet rarely if ever in clinical practice in most countries, the reasons cited being lack of evidence for its usefulness, lack of specificity, or its high cost/effectiveness ratio. Given the difficulty of finding a consensus tool for the diagnosis of malnutrition, there is every reason to consider such a simple and inexpensive marker as TTR. However, further studies are needed to define and unify international guidelines on the use of TTR in terms of inflammation level and the associated cut-off values.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-22104-4

Objectives Lean body mass (LBM) is an important prognostic factor in patients with cancer. Although the L3–computed tomography (CT) scan is considered a reference method for assessment, a convenient and easily available method for longitudinal follow-up is required. Although bioelectrical impedance analysis (BIA) is widely used, its accuracy is questioned; plasma creatinine-to-cystatin C (CC) ratio could be an attractive alternative. The aim of this study was to evaluate the ability of the CC ratio and BIA to detect myopenia in patients with cancer compared with the use of the CT scan as a standard. Methods Patients with any kind of cancer had body composition evaluation by CT scan, BIA, and CC. Statistical analysis included correlation test, Bland–Altman, and receiver operating characteristic curve analysis. Results Forty-four patients (14 women) were included. Of the participants, 59% had myopenia on CT scan. Both BIA LBM and CC ratio were well correlated with CT scan LBM (r = 0.763 and 0.648, respectively) but concordance analysis revealed a 3-kg constant bias toward BIA compared with CT scan. In terms of ability to detect myopenia, areas under the curve (AUC) for BIA were 0.675 and 0.388 for men and women, respectively. For CC ratio, AUCs were 0.813 and 0.673. Conclusion This study demonstrated that LBM assessed by the CC ratio or BIA is well correlated with that determined by L3-CT scan. The ability of the CC ratio to detect myopenia was better than that of BIA. Findings from the present study demonstrated that CC ratio can be conveniently used in patients with cancer as a reliable biomarker of muscularity.

The past year has shown that obesity is a risk factor for severe complications of SARS-CoV-2 infection. Excess fat mass during obesity is known to be a risk factor for chronic diseases but also for severe infections and infectious complications. We have focused here on the elements responsible for this particular susceptibility to infections and more specifically to COVID-19. Excess fat is, in itself, responsible for alterations of the immune system by disrupting the production and function of immune cells. Indeed, hypertrophic adipocytes produce more pro-inflammatory adipokines (including cytokines). The increase in their apoptosis induces a release of pro-inflammatory compounds into the circulation and a recruitment of pro-inflammatory macrophages into the adipose tissue. A chronic systemic inflammatory state is then observed. In addition, diet, apart from its role in the development of adipose tissue, can also affect the immune system, with excess simple sugars and saturated fats exerting pro-inflammatory effects. This inflammation, the adipokines released by the adipocytes, and the infiltration of lipids into the lymphoid organs affects the production of immune cells and, directly, the functions of these cells. The alteration of the immune system increases the risk of infection as well as complications, including secondary bacterial infections and septic states, and increases infection-related mortality. During COVID-19, the chronic inflammatory state promotes the cytokine shock, characteristic of severe forms, caused in particular by excessive activation of the NLRP3 inflammasome. Furthermore, in obese subjects, the already present endothelial dysfunction will render endothelial inflammation (endotheliitis) due to viral infiltration all the more severe. Added to this is a state of hypercoagulability and a decrease in respiratory capacity, leading to a risk of severe COVID-19 with cardiovascular complications, acute respiratory distress syndrome, and disseminated intravascular coagulation, which can lead to multiple organ failure and even death.

Summary Background & aims Metastatic non-small cell lung cancer (NSCLC) is the first cause of cancer death worldwide. Increased resting energy expenditure (REE) is frequent among cancer patients and may contribute to cancer cachexia. The aim of this study was to examine the prognostic value of increased REE in metastatic NSCLC patients. Methods This observational study was conducted between June 2012 and November 2017 in the outpatient unit of the oncology department of Cochin hospital, Paris. Consecutive patients with newly diagnosed stage IV NSCLC underwent measurement of REE by indirect calorimetry before treatment initiation. Uni- and multivariate analysis of overall survival (OS, Cox models) included age, sex, smoking habit, histological subtype, performance status, body mass index, weight loss, albumin and CRP levels and the ratio of measured REE to the REE predicted by the Harris Benedict formula (mREE/pREE). Results 144 patients were enrolled: mean age 64 years, 63% male, 90% non-squamous carcinoma, including 17% with ALK/EGFR alteration. In univariate analysis, tobacco consumption (p = 0.007), histo-molecular subtype (p vs ≤ 120%: HR = 2.16, p and ≤120%, respectively. In multivariate analysis, histo-molecular subtype (non-squamous ALK/EGFR mutated vs squamous carcinoma: HR = 0.25, p = 0.006), weight loss (>vs ≤ 5%: HR = 1.98, p = 0.004), albumin (≥vs vs ≤120%: HR = 1.90, p = 0.004) were identified as independent prognostic factors. Conclusions Elevated resting energy expenditure emerges as an independent prognostic factor in metastatic NSCLC.

The prevalence of cognitive decline is increasing as the ageing population is considerably growing. Restricting this age-associated process has become a challenging public health issue. The age-related increase in oxidative stress plays a major role in cognitive decline, because of its harmful effect on functional plasticity of the brain, such as long-term potentiation (LTP). Here, we show that citrulline (Cit) has powerful antioxidant properties that can limit ex vivo oxidative stress-induced LTP impairment in the hippocampus. We also illustrate that a three-month Cit supplementation has a protective effect on LTP in aged rats in vivo. The identification of a Cit oxidation byproduct in vitro suggests that the antioxidant properties of Cit could result from its own oxidation. Cit supplementation may be a promising preventive nutritional approach to limit age-related cognitive decline.

Alterations of nutritional and performance status (PS) are associated with higher risk of chemotherapy toxicity. Increased resting energy expenditure (REE) is frequent in cancer patients and may contribute to cachexia. We investigated whether abnormal energetic metabolism could predict early acute limiting toxicities (ELT) of anticancer treatments.In this observational monocentric study, REE was measured by indirect calorimetry before treatment initiation. Based on the ratio of measured REE to REE predicted by the Harris-Benedict formula, patients were classified as hypometabolic (90%), normometabolic (90-110%) or hypermetabolic (110%). Body mass index, weight loss, PS, albumin, transthyretin, C-reactive protein (CRP) and muscle mass (CT-scan) were studied. Were defined as ELT any unplanned hospitalization or any adverse event leading to dose reduction or discontinuation during the first cycle of treatment.We enrolled 277 patients: 76% had metastatic disease; 89% received chemotherapy and 11% targeted therapy; 29% were normometabolic, 51% hypermetabolic and 20% hypometabolic. Fifty-nine patients (21%) experienced an ELT. Toxicity was associated with abnormal metabolism (vs normal: OR = 2.37 [1.13-4.94], p = 0.023), PS (2-3 vs 0-1: OR = 2.04 [1.12-3.74], p = 0.023), albumin (35 vs ≥35 g/l: OR = 2.39 [1.03-5.54], p = 0.048), and inflammation (CRP ≥10 vs10 mg/l: OR = 2.43 [1.35-4.38], p = 0.004). To predict toxicity, the most sensitive parameter was the REE (83%) followed by PINI (63%), GPS (59%), CRP (55%), PS (41%), NRI (37%), and albumin (16%). In multivariate analysis, elevated CRP was an independent predictor of toxicity (p = 0.047).Abnormal basal energy metabolism identifies patients at higher risk of treatment-related acute complications.

Objective Age-associated sarcopenia is due to anabolic resistance to feeding. Muscle protein synthesis is improved by fast proteins (e.g., lactoserum), which increase peripheral amino acid (AA) bioavailability more rapidly than slow proteins (e.g., casein), and by citrulline. Citrulline, which limits splanchnic sequestration of AA, may more effectively increase peripheral AA bioavailability when combined with lactoserum than with casein when administered as an oral nutritional protein supplement. Methods In this study, 25 fasted aged rats received a single gavage administration of lactoserum or casein 0.4 g/kg, alone or with citrulline 0.4 g/kg, and AA pharmacokinetics, glucose, insulin, triglycerides, and insulin-like growth factor 1 (IGF1) were monitored for 4 h. At 4 h, muscle protein and AA contents and protein synthesis activation were measured. Results While lactoserum was associated with higher AA availability, citrulline exerts only limited effects on the plasma profile of AAs from the two proteins. Maximum plasma citrulline was reached earlier with casein (T90 min) than with lactoserum (T120 min). A protein x citrulline interaction was observed for some plasma and muscle AA levels with a significant activation of mechanistic target of rapamycin complex 1 (mTORC1) signaling suggesting higher anabolism with the combination of citrulline and lactoserum. Lower plasma and muscle AA levels with citrulline and lactoserum compared to lactoserum alone suggest a greater AA utilization in a context of muscle anabolic signaling activation. Conclusion Provision of a citrulline-lactoserum combination as a nutritional supplement could therefore be beneficial in terms of muscle protein balance and prevention of sarcopenia. Further studies are warranted to evaluate the efficacy of this combination.

Objective In critically ill patients, acute injury alters gut function, causing greater risk for sepsis and malnutrition. Peptide-enriched diets may promote nitrogen absorption, whereas ω3-enriched diets reduce alterations in gut barrier function. The aim of this study was to assess the effectiveness of a peptide- and ω3-enriched diet on the metabolic response to injury and the gut barrier function in a model of prolonged catabolism in the rat. Given the intestinal trophic effect of glutamine, we tested for a synergistic effect of glutamine. Methods We randomized 40 male Sprague-Dawley rats (250 g) into four groups to enterally receive a standard high-protein diet (S), or a peptide- and ω3-enriched diet either alone (IMN) or supplemented with glutamine and alanine supplied as dipeptide (DIP) or as free amino acids (AAs) for 4 d. Metabolic response to injury was induced by turpentine injections on days 1 and 3. At sacrifice, nutritional and inflammatory biomarkers and intestinal and liver function were assessed. Results Weight gain (+45–62%) and nitrogen balance (+33–56%) were significantly higher in all groups than in the S group. In jejunal mucosa, total glutathione was significantly higher (+20–30%) and myeloperoxidase activity significantly lower in all groups compared with the S group. Hepatic triacylglycerol content was significantly lower in the AA (0.30 ± 0.04 μM/g) and DIP (0.43 ± 0.08 μM/g) groups than in the S group (0.71 ± 0.08 μM/g). Conclusions In this model of prolonged catabolism, compared with a standard diet, a peptide- and ω3-enriched diet improved metabolic response to injury, with better nitrogen balance and weight recovery, and decreased intestinal myeloperoxidase activity. Only marginal additional effects of glutamine supplementation were observed with decreased hepatic fat content.

Steatosis can sensitise the liver to various challenges and favour the development of non-alcoholic fatty liver disease (NAFLD). In this context, fructose feeding promotes endotoxin translocation from the gut, contributing to disease progression via an inflammatory process. Citrulline is protective against fructose-induced NAFLD; we hypothesised that this property might be related to its anti-inflammatory and antioxidative action against endotoxin-induced hepatic injuries. This hypothesis was evaluated in a model of perfused liver isolated from NAFLD rats. Male Sprague–Dawley rats (n30) were fed either a standard rodent chow or a 60 % fructose diet alone, or supplemented with citrulline (1 g/kg per d) for 4 weeks. After an evaluation of their metabolic status, fasted rats received an intraperitoneal injection of lipopolysaccharide (LPS) (2·5 mg/kg). After 1 h, the livers were isolated and perfused for 1 h to study liver function and metabolism, inflammation and oxidative status.In vivo, citrulline significantly decreased dyslipidaemia induced by a high-fructose diet and insulin resistance. In the isolated perfused rat livers, endotoxaemia resulted in higher cytolysis (alanine aminotransferase release) and higher inflammation (Toll-like receptor 4) in livers of fructose-fed rats, and it was prevented by citrulline supplementation. Oxidative stress and antioxidative defences were similar in all three groups. Amino acid exchanges and metabolism (ammonia and urea release) were only slightly different between the three groups. In this context of mild steatosis, our results suggest that fructose-induced NAFLD leads to an increased hepatic sensitivity to LPS-induced inflammation. Citrulline-induced restriction of the inflammatory process may thus contribute to the prevention of NAFLD.

N-carbamoyl putrescine (NCP), the decarboxylation derivative of citrulline, metabolically related to polyamines, may exert biological effects in mammals. The aim of this study was (i) to evaluate the nutritional properties of NCP in healthy rats and (ii) to determine the effect of NCP administration on muscle metabolism in malnourished old rats. The nutritional properties of NCP were first evaluated in 20 8-week-old male rats randomized to receive for two weeks a standard diet either alone (C group) or supplemented with NCP, 5 or 50 mg/kg/d. In a second study, 29 malnourished 18-month-old male rats were studied either before or after a 4-day refeeding with a standard diet either alone (REN group) or supplemented with NCP, 1 or 10 mg/kg/d. NCP had no effect on weight gain and body composition in either of the two studies. In healthy rats, muscle protein content was significantly increased in the soleus with NCP 5 mg/kg/d. A decrease in plasma glutamine and kidney spermine was observed at the 50 mg/kg/d dose, otherwise, no significant changes in plasma chemistry and tissue polyamines were observed. In malnutrition-induced sarcopenic old rats, refeeding with NCP 10 mg/kg/d was associated with higher tibialis weight and a trend for increased protein content in extensor digitorum longus (EDL). While the muscle protein synthesis rate was similar between groups, ribosomal protein S6 kinase was increased in tibialis and higher in the EDL in NCP-treated rats. The muscle RING-finger protein-1 expression was decreased in tibialis and urinary 3-methyl-histidine to creatinine ratio slightly lower with the supply of NCP. However, this initial period of refeeding was also associated with elevated fasted plasma triglycerides and glucose, significant in NCP groups, suggesting glucose intolerance and possibly insulin resistance. NCP was well-tolerated in healthy young-adults and in malnourished old rats. In healthy adults, NCP at 5 mg/kg/d induced a significant increase in protein content in the soleus, a type I fiber-rich muscle. In malnourished old rats, NCP supply during refeeding, may help to preserve lean mass by limiting protein breakdown, however, these effects may be limited in our model by a possible immediate refeeding-associated glucose intolerance.

N-carbamoyl putrescine (NCP), the decarboxylation derivative of citrulline, metabolically related to polyamines, may exert biological effects in mammals. The aim of this study was (i) to evaluate the nutritional properties of NCP in healthy rats and (ii) to determine the effect of NCP administration on muscle metabolism in malnourished old rats. The nutritional properties of NCP were first evaluated in 20 8-week-old male rats randomized to receive for two weeks a standard diet either alone (C group) or supplemented with NCP, 5 or 50 mg/kg/d. In a second study, 29 malnourished 18-month-old male rats were studied either before or after a 4-day refeeding with a standard diet either alone (REN group) or supplemented with NCP, 1 or 10 mg/kg/d. NCP had no effect on weight gain and body composition in either of the two studies. In healthy rats, muscle protein content was significantly increased in the soleus with NCP 5 mg/kg/d. A decrease in plasma glutamine and kidney spermine was observed at the 50 mg/kg/d dose; otherwise, no significant changes in plasma chemistry and tissue polyamines were observed. In malnutrition-induced sarcopenic old rats, refeeding with NCP 10 mg/kg/d was associated with higher tibialis weight and a trend for increased protein content in extensor digitorum longus (EDL). While the muscle protein synthesis rate was similar between groups, ribosomal protein S6 kinase was increased in tibialis and higher in the EDL in NCP-treated rats. The muscle RING-finger protein-1 expression was decreased in tibialis and urinary 3-methyl-histidine to creatinine ratio slightly lower with the supply of NCP. However, this initial period of refeeding was also associated with elevated fasted plasma triglycerides and glucose, significant in NCP groups, suggesting glucose intolerance and possibly insulin resistance. NCP was well-tolerated in healthy young-adults and in malnourished old rats. In healthy adults, NCP at 5 mg/kg/d induced a significant increase in protein content in the soleus, a type I fiber-rich muscle. In malnourished old rats, NCP supply during refeeding, may help to preserve lean mass by limiting protein breakdown; however, these effects may be limited in our model by a possible immediate refeeding-associated glucose intolerance.

Purpose of review Protein homeostasis is crucial for maintaining cell functions. Citrulline, an endogenous amino acid, is considered as an efficient source of arginine at systemic and cellular level. Accumulating evidence, obtained from citrulline supplementation studies, suggest anabolic properties especially in malnourished rodents and human. Although these studies might suggest a key role for citrulline in protein homeostasis, the supraphysiological concentrations of citrulline do not allow to conclude on a physiological role. This review aimed to assess the role of endogenous citrulline production on protein homeostasis. Recent findings According to recent studies, endogenous citrulline, through its regulating effect on nitric oxide production, seems to play a key role in regulating endothelial and immune functions. We can assume that citrulline-dependent endothelial vasodilation could improve organ perfusion and thus amino acid and insulin supply. Furthermore, citrulline regulates immune cells and thus could regulate inflammation and indirectly protein metabolism. Summary Although we have currently no direct evidence of a regulating role of endogenous citrulline production on protein homeostasis, we can hypothesize that physiologically through its role in endothelial and immune function, citrulline could indirectly participate to protein homeostasis.

Arginine (Arg) is a conditionally essential amino acid that plays key roles in nitrogen metabolism and ureagenesis, in cellular multiplication, in energy metabolism, and in endothelial function. In healthy adults, besides adaptation to its dietary supply, Arg homeostasis depends on its synthesis thanks to a gut–kidney cooperation and on its recycling from citrulline. If quantitatively its most important use is protein synthesis, qualitatively, its role as precursor of nitric oxide (°NO) and polyamines is crucial. Endothelial function is based on the synthesis of °NO by endothelial °NO synthase. It is therefore compromised when the availability of its substrate Arg decreases or when the activity of the enzyme decrease as insulin resistance develops. Arg supplementation would thus be beneficial in situations of endothelial dysfunction by increasing Arg availability or indirectly via Arg-induced improvement in insulin sensitivity. Moreover, Arg may also act by its effects on other component of the metabolic syndrome. Arg could thus improve muscle protein homeostasis first through this vascular effect and increased delivery of substrates and anabolic factor to the muscle. In addition, Arg is a direct activator of mammalian/mechanistic target of rapamycin key player in the response of muscle protein synthesis to anabolic stimulus. Here also, Arg supplementation does not seem to affect protein homeostasis in a healthy situation; however, in situations of insulin resistance, it may have a protective effect against muscle loss. Arg may play a role in the adaptation to exercise. While acute or chronic Arg administration has no effect on exercise performance in healthy subjects, it may increase maximal aerobic capacity in patients with cardiovascular diseases. Last Arg could be protective on muscle protein metabolism during stress-induced hypercatabolism. First, it could improve immune function and this in part supported by clinical studies. Second, it could act on tissue healing and muscle repair. Third, it could promote muscle protein anabolism either via an improvement in the secretion and action of growth factor or through a direct action on the muscle. Unfortunately, human data supporting these effects are lacking.

The high worldwide prevalence of nonalcoholic fatty liver disease (NAFLD) makes it a major public health issue. Amino acids offer a promising approach for its prevention, and several experimental studies highlight the nutritional importance of citrulline in this setting. The purpose of this review is to discuss the potential interest of citrulline in the prevention and treatment of NAFLD.Current findings shed light on the role of the gut-liver, adipose tissue-liver, and muscle-liver axes in NAFLD progression. Recent experimental studies have produced evidence for a role of citrulline in controlling the pathophysiological mechanisms involved in NAFLD through its action on these three axes. Data are needed to distinguish between direct and indirect effects of citrulline on the liver and between a specific effect and a nitrogen supply-related effect.Good level of experimental evidence suggests that citrulline supply may be associated with an attenuation of NAFLD development, but further human studies are now needed to support these findings. This review may help define novel strategies to control fatty liver diseases.

Impairments of intestinal barrier function are discussed as risk factors for the development and progression of non-alcoholic fatty liver disease (NAFLD). Studies suggest an association between arginine/citrulline homeostasis and the development of liver damages. Here, the effect of an oral l-citrulline (Cit) supplement on the development of a Western-style diet (WSD)-induced NAFLD was determined in mice. Female 6- to 8-week-old C57BL/6J mice were either pair-fed a liquid Western-style or control diet (C) ± 2.5 g/kg bodyweight Cit for 6 weeks (C + Cit or WSD + Cit). Indices of liver damage, glucose metabolism, intestinal barrier function and NO synthesis were measured. While bodyweight gain was similar between groups, markers of glucose metabolism like fasting blood glucose and HOMA index and markers of liver damage like hepatic triglyceride levels, number of neutrophils and plasminogen activator inhibitor-1 protein levels were significantly lower in WSD + Cit-fed mice when compared to WSD-fed mice only. Protein levels of the tight junction proteins occludin and zonula occludens-1 in duodenum were significantly lower in mice fed a WSD when compared to those fed a WSD + Cit (−~70 and −~60 %, respectively, P

International audience; Objective: Muscle net catabolism, as seen after severe trauma or sepsis or in postoperative situations, is mediated by hormones (e.g., cortisol) and proinflammatory cytokines (e.g., tumor necrosis factor alpha [TNF-α]). Specific amino acids may be able to limit this muscle mass loss. Citrulline (CIT) stimulates muscle protein synthesis in various situations, but little data exist on hypercatabolic situations and the effects on protein breakdown are unknown. Our aim was to assess the effect of CIT on protein turnover in an in vitro model of muscle hypercatabolism.Methods: Myotubes derived from C2C12 myoblasts were treated with 150 nM dexamethasone (DEX), 10 ng/mL TNF-α, or 0.006% ethanol (as control [CON]) for 24 h. Subsequently, myotubes were incubated with or without 5 mM CIT for 6 h. Muscle protein synthesis rate was evaluated by the surface sensing of translation method and by l-[3,5-3H]tyrosine (Tyr) incorporation. The muscle protein breakdown rate was evaluated from Tyr release into culture medium. CIT action was analyzed by non-parametric Kruskal-Wallis and Mann-Whitney tests.Results: CIT treatment significantly increased protein synthesis rates compared with the DEX or TNF-α group (surface sensing of translation method; DEX + CIT versus DEX; P = 0.03 and TNF-α+CIT versus TNF-α; P = 0.05) and significantly decreased protein breakdown rate in the CON and DEX groups (CON + CIT versus CON; P = 0.05 and DEX + CIT versus DEX; P = 0.05).Conclusions: CIT treatment regulated muscle protein turnover in an in vitro model of muscle net catabolism. Exploring the underlying mechanisms would also be of interest.

BACKGROUND: Insulin resistance after surgery hampers recovery. Oxidative stress is shown to be involved in the occurrence of postoperative insulin resistance. Preoperative carbohydrate-rich oral nutrition supplements reduce but do not prevent insulin resistance. The aim of the present study was to investigate the effect of a carbohydrate-, glutamine-, and antioxidant-enriched preoperative oral nutrition supplement on postoperative insulin resistance.METHODS: A double-blind randomized controlled pilot study in 18 patients with rectal cancer, who received either the supplement (S) or the placebo (P) 15, 11, and 4 hours preoperatively, was conducted. Insulin sensitivity was studied prior to surgery and on the first postoperative day using a hyperinsulinemic euglycemic 2-step clamp.RESULTS: Hepatic insulin sensitivity (insulin-mediated suppression of glucose production) decreased significantly after surgery in both groups, with no differences between the groups. Peripheral insulin sensitivity (glucose rate of disappearance, Rd) was significantly decreased after surgery in both groups (S: 37.2 [19.1-50.9] vs 20.6 [13.9-27.9]; P: 23.8 [15.7-35.5] vs 15.3 [12.6-19.1] µmol/kg·min) but less pronounced in the supplemented group ( P = .04). The percentage decrease in glucose Rd did not differ between the groups. Adipose tissue insulin sensitivity (insulin-mediated suppression of plasma free fatty acids) decreased to the same extent after surgery in both groups.CONCLUSION: Rectal cancer surgery induced profound insulin resistance, affecting glucose and fatty acid metabolism. The preoperative nutrition supplement somewhat attenuated but did not prevent postoperative peripheral insulin resistance.

Background Fructose induces nonalcoholic fatty liver disease (NAFLD). Citrulline (Cit) may exert a beneficial effect on steatosis. Objective We compared the effects of Cit and an isonitrogenous mixture of nonessential amino acids (NEAAs) on fructose-induced NAFLD. Methods Twenty-two male Sprague Dawley rats were randomly assigned into 4 groups (n = 4-6) to receive for 8 wk a 60% fructose diet, either alone or supplemented with Cit (1 g · kg(-1) · d(-1)), or an isonitrogenous amount of NEAAs, or the same NEAA-supplemented diet with starch and maltodextrin instead of fructose (controls). Nutritional and metabolic status, liver function, and expression of genes of hepatic lipid metabolism were determined. Results Compared with controls, fructose led to NAFLD with significantly higher visceral fat mass (128%), lower lean body mass (-7%), insulin resistance (135%), increased plasma triglycerides (TGs; 67%), and altered plasma amino acid concentrations with decreased Arg bioavailability (-27%). This was corrected by both NEAA and Cit supplementation. Fructose caused a 2-fold increase in the gene expression of fatty acid synthase (Fas) and 70% and 90% decreases in that of carnitine palmitoyl-transferase 1a and microsomal TG transfer protein via a nearly 10-fold higher gene expression of sterol regulatory element-binding protein-1c (Srebp1c) and carbohydrate-responsive element-binding protein (Chrebp), and a 90% lower gene expression of peroxisome proliferator-activated receptor α (Ppara). NEAA or Cit supplementation led to a Ppara gene expression similar to controls and decreased those of Srebp1c and Chrebp in the liver by 50-60%. Only Cit led to Fas gene expression and Arg bioavailability similar to controls. Conclusion In our rat model, Cit and NEAAs effectively prevented fructose-induced NAFLD. On the basis of literature data and our findings, we propose that NEAAs may exert their effects specifically on the liver, whereas Cit presumably acts at both the hepatic and whole-body level, in part via improved peripheral Arg metabolism.

Background and Purpose NO is a crucial regulator of energy and lipid metabolism, whose homeostasis is compromised during obesity. Combination of citrulline and atorvastatin potentiated NO production in vitro. Here we have assessed the effects of this combination in mice with diet-induced obesity (DIO). Experimental Approach C57BL/6J male mice were given a standard diet (control) or a high fat–high sucrose diet (DIO) for 8 weeks. DIO mice were then treated with DIO alone, DIO with citrulline, DIO with atorvastatin or DIO with citrulline and atorvastatin (DIOcit–stat) for 3 weeks. Thereafter, body composition, glucose tolerance, insulin sensitivity and liver fat metabolism were measured. Key Results DIOcit–stat mice showed lower body weight, fat mass and epididymal fat depots compared with other DIO groups. Unlike other DIO groups, glucose tolerance and insulin sensitivity of DIOcit–stat, along with blood glucose and insulin concentrations in response to feeding, were restored to control values. Refeeding-induced changes in liver lipogenic activity were also reduced in DIOcit–stat mice compared with those of DIO animals. This was associated with decreased gene expression of the transcription factor SREBP-1, liver X receptor α, ChREBP and of target lipogenic enzymes in the liver of DIOcit–stat mice compared with those of other DIO groups. Conclusions and Implications The citrulline–atorvastatin combination prevented fat mass accumulation and maintained glucose homeostasis in DIO mice. Furthermore, it potentiated inhibition of hepatic de novo lipogenesis activity. This combination has potential for preservation of glucose homeostasis in patients receiving statin therapy.

Among various factors, such as an unhealthy diet or a sedentarity lifestyle, excessive fructose consumption is known to favor nonalcoholic fatty liver disease (NAFLD), as fructose is both a substrate and an inducer of hepatic de novo lipogenesis. The present review presents some well‐established mechanisms and new clues to better understand the pathophysiology of fructose‐induced NAFLD. Beyond its lipogenic effect, fructose intake is also at the onset of hepatic inflammation and cellular stress, such as oxidative and endoplasmic stress, that are key factors contributing to the progression of simple steatosis to nonalcoholic steatohepatitis (NASH). Beyond its hepatic effects, this carbohydrate may exert direct and indirect effects at the peripheral level. Excessive fructose consumption is associated, for example, with the release by the liver of several key mediators leading to alterations in the communication between the liver and the gut, muscles, and adipose tissue and to disease aggravation. These multifaceted aspects of fructose properties are in part specific to fructose, but are also shared in part with sucrose and glucose present in energy– dense beverages and foods. All these aspects must be taken into account in the development of new therapeutic strategies and thereby to better prevent NAFLD.

High fructose intake causes hepatic insulin resistance and increases postprandial blood glucose, lactate, triglyceride, and uric acid concentrations. Uric acid may contribute to insulin resistance and dyslipidemia in the general population. In patients with hereditary fructose intolerance, fructose consumption is associated with acute hypoglycemia, renal tubular acidosis, and hyperuricemia. We investigated whether asymptomatic carriers for hereditary fructose intolerance (HFI) would have a higher sensitivity to adverse effects of fructose than would the general population. Eight subjects heterozygous for HFI (hHFI; 4 men, 4 women) and 8 control subjects received a low-fructose diet for 7 d and on the eighth day ingested a test meal, calculated to provide 25% of the basal energy requirement, containing 13C-labeled fructose (0.35 g/kg), glucose (0.35 g/kg), protein (0.21 g/kg), and lipid (0.22 g/kg). Glucose rate of appearance (GRa, calculated with [6,6-2H2]glucose), fructose, net carbohydrate, and lipid oxidation, and plasma triglyceride, uric acid, and lactate concentrations were monitored over 6 h postprandially. Postprandial GRa, fructose, net carbohydrate, and lipid oxidation, and plasma lactate and triglyceride concentrations were not significantly different between the 2 groups. Postprandial plasma uric acid increased by 7.2% compared with fasting values in hHFI subjects (P

Resume Le patient hospitalise en reanimation, quand il n’est pas deja denutri a l’admission, presente un risque eleve de denutrition du fait de sa possible incapacite a couvrir spontanement ses besoins nutritionnels et compte tenu de la majoration de ceux-ci induite par l’agression. L’evaluation nutritionnelle initiale permet, tout en disposant d’une reference de depart, de definir l’urgence de l’assistance nutritionnelle et le risque de complications induites par la denutrition. Une fois les modalites de l’assistance nutritionnelle definies et celle-ci mise en route, il est bien entendu necessaire de suivre son efficacite et le cas echeant sa tolerance. Les marqueurs biologiques dans cette evaluation et ce suivi nutritionnels seront tout d’abord deux proteines seriques, l’albumine et la transthyretine, plutot marqueur pronostique pour la premiere et marqueur de suivi pour la seconde, tres largement accessibles dans les laboratoires de biologie. L’evaluation du capital proteique et de sa dynamique pourra, pour le plus simple, recourir au suivi du bilan azote, de preference a partir de la mesure de l’azote total urinaire, qui ne donne qu’une image globale du metabolisme proteique ou, pour les laboratoires possedant l’equipement chromatographique necessaire, l’analyse des acides amines sanguins (rapport phenylalanine/tyrosine) et urinaires (3-methyl-histidine) qui permettra d’evaluer le catabolisme proteique. Enfin, l’etude de l’aminoacidogramme plasmatique complet pourrait etre une piste d’avenir pour une adaptation individualisee de l’apport nutritionnel.

Resume Avec l’augmentation du nombre de personnes âgees dependantes, la denutrition au sein de cette population est devenue un probleme majeur de societe puisqu’elle impacte directement la qualite de vie des sujets et elle est un facteur de morbi-mortalite. Or, l’une des caracteristiques de la personne âgee est qu’elle presente specifiquement une resistance a la renutrition. Les causes en sont multiples, faisant intervenir en particulier une augmentation de l’utilisation splanchnique des acides amines (AA), phenomene appele sequestration splanchnique des AA. La citrulline, un acide amine encore peu etudie pour ses proprietes nutritionnelles, echappe totalement a cette sequestration splanchnique et possede la propriete de stimuler la synthese proteique musculaire. Cette activation de la proteosynthese musculaire s’accompagne d’une accretion proteique, d’une augmentation de la force musculaire et d’une augmentation de la motricite. La citrulline semble donc etre un candidat particulierement prometteur pour lutter contre la denutrition chez la personne âgee.

Dietary arginine (Arg) supplementation has been proposed to have positive effects on the development of liver diseases. In the present study, we investigate if an oral Arg supplementation in diet protects mice fed a fructose, fat and cholesterol enriched Western-style diet (WSD) from the development of non-alcoholic steatohepatitis (NASH). Female C57BL/6J mice were fed a liquid control diet or a liquid WSD ± Arg (2.49 g/kg body weight/day) for 6 weeks. Indices of liver injury, glucose metabolism and intestinal permeability were determined. While Arg supplementation had no effects on body weight gain, fasting blood glucose levels were significantly lower in WSD+Arg-fed mice than in C+Arg-fed animals. WSD-fed mice developed liver steatosis accompanied with inflammation, both being significantly attenuated in WSD+Arg-fed mice. These effects of Arg supplementation went along with a protection against WSD-induced decreased tight junction protein levels in the upper parts of the small intestine, increased levels of bacterial endotoxin in portal plasma as well as increased hepatic toll-like receptor-4 mRNA and 4-hydroxynonenal protein adduct levels. In conclusion, Arg supplementation may protect mice from the development of NASH. Electronic supplementary material The online version of this article (doi:10.1007/s00726-017-2423-4) contains supplementary material, which is available to authorized users.

A Western diet induces insulin resistance, liver steatosis (non-alcoholic fatty liver disease (NAFLD)) and intestinal dysbiosis, leading to increased gut permeability and bacterial translocation, thus contributing to the progression of NAFLD to non-alcoholic steatohepatitis. In the present study, we sought, in a model of Western diet-induced NAFLD, to determine whether citrulline (Cit), an amino acid that regulates protein and energy metabolism, could decrease Western diet-induced liver injuries, as well as the mechanisms involved. Sprague–Dawley rats were fed a high-fat diet (45 %) and fructose (30 %) in drinking water or a control diet associated with water (group C) for 8 weeks. The high-fat, high-fructose diet (Western diet) was fed either alone (group WD) or with Cit (1 g/kg per d) (group WDC) or an isonitrogenous amount of non-essential amino acids (group WDA). We evaluated nutritional and metabolic status, liver function, intestinal barrier function, gut microbiota and splanchnic inflammatory status. Cit led to a lower level of hepatic TAG restricted to microvesicular lipid droplets and to a lower mRNA expression of CCAAT-enhancer-binding protein homologous protein, a marker of endoplasmic reticulum stress, of pro-inflammatory cytokines Il6 (PTnfα, and of toll-like receptor 4 (Tlr4) (PTnfα and Tlr4 expressions) and increased claudin-1 protein expression. This was associated with higher levels of Bacteroides/Prevotella compared with rats fed the Western diet alone. Cit improves Western diet-induced liver injuries via decreased lipid deposition, increased insulin sensitivity, lower inflammatory process and preserved antioxidant status. This may be related in part to its protective effects at the gut level.

The preservation or restoration of muscle mass is of prime importance for healthy aging. However, aging has been repeatedly shown to be associated with resistance of muscle to the anabolic effects of feeding. Leucine supplementation has been proposed as a possible strategy because of its regulatory role on protein homeostasis. Indeed, it acts independently of growth factors and leads to enhanced cap-dependent mRNA translation initiation and increased protein synthesis. Leucine acts as a signaling molecule directly at the muscle level via the activation of mammalian/mechanistic target of rapamycin complex 1 (mTORC1). However, in aged muscle, mTORC1 activation seems to be impaired, with decreased sensitivity and responsiveness of muscle protein synthesis to amino acids, whereas the phosphorylation state of several components of this signaling pathway appears to be higher in the basal state. This may stem from specific age-related impairment of muscle signaling and from decreased nutrient and growth factor delivery to the muscle. Whether aging per se affects mTORC1 signaling remains to be established, because aging is frequently associated with inadequate protein intake, decreased insulin sensitivity, inactivity, inflammatory processes, etc. Whatever its origin, this anabolic resistance to feeding can be mitigated by quantitative and qualitative manipulation of protein supply, such as leucine supplementation; however, there remains the question of possible adverse effects of long-term, high-dose leucine supplementation in terms of insulin resistance and tumorigenesis.

The review assesses the utility of supplementing parenteral or enteral nutrition of ICU patients with each of five specific amino acids that display pharmacological properties. Specifying indications implies also stating contraindications.Combined supplementation of amino acids with ω3-fatty acids and/or trace elements (immune-enhancing diets) will not be considered in this review because these mixtures do not allow the role of amino acids in the effect (positive or negative) of the mixture to be isolated, and so cannot show whether or not supplementation of a given amino acid is indicated.After decades of unbridled use of glutamine (GLN) supplementation in critically ill patients, recent large trials have brought a note of caution, indicating for example that GLN should not be used in patients with multiple organ failure. Yet these large trials do not change the conclusions of recent meta-analyses. Arginine (ARG), as a single dietary supplement, is probably not harmful in critical illness, in particular in a situation of ARG deficiency syndrome with low nitric oxide production. Citrulline supplementation strongly improves microcirculation in animal models with gut injury, but clinical studies are lacking. Taurine has a potent protective effect against ischemic reperfusion injury.Amino acid-based pharmaconutrition has displayed familiar 'big project' stages: enthusiasm (citrulline and taurine), doubt (GLN), hunt for the guilty (ARG), and backpedalling (leucine). Progress in this field is very slow, and sometimes gives way to retreat, as demonstrated by recent large trials on GLN supplementation.

Background Immunonutrition in sepsis, including n-3 poly-unsaturated fatty acids (PUFAs) or L-arginine supplementation, is a controversial issue that has yielded a great number of studies for the last thirty-five years, and the conclusions regarding the quantity and quality of this support in patients are deceiving. The aim of the present experimental study is to investigate the effects of a pretreatment with enteral nutrition enriched with n-3 PUFAs or L-arginine on vascular dysfunctions, inflammation and oxidative stress during septic shock in rats. Design Rats were fed with enteral Peptamen® HN (HN group), Peptamen® AF containing n-3 PUFAs (AF group) or Peptamen® AF enriched with L-arginine (AFA group). On day 4, peritonitis by cecal ligation and puncture (CLP) was performed. Rats were resuscitated (H18) once septic shock was established. After a 4-hour resuscitation, vessels and organs were harvested to assess inflammation, superoxide anion, nitric oxide and prostacyclin levels. Ex-vivo vascular reactivity was also performed. Results Compared to CLP-AF or CLP-HN groups, 47.6% of CLP-AFA rats died before the beginning of hemodynamic measurements (vs. 8.0% and 20.0% respectively, p

Obese and type 2 diabetic patients present metabolic disturbance-related alterations in nonspecific immunity, to which the decrease in their plasma arginine contributes. Although diabetes-specific formulas have been developed, they have never been tested in the context of an acute infectious situation as can be seen in intensive care unit patients. Our aim was to investigate the effects of a diabetes-specific diet enriched or not with arginine in a model of infectious stress in a diabetes and obesity situation. As a large intake of arginine may be deleterious, this amino acid was given in graded fashion.Randomized, controlled experimental study.University research laboratory.Zucker diabetic fatty rats.Gastrostomized Zucker diabetic fatty rats were submitted to intraperitoneal lipopolysaccharide administration and fed for 7 days with either a diabetes-specific enteral nutrition without (G group, n=7) or with graded arginine supply (1-5 g/kg/day) (GA group, n=7) or a standard enteral nutrition (HP group, n=10).Survival rate was better in G and GA groups than in the HP group. On day 7, plasma insulin to glucose ratio tended to be lower in the same G and GA groups. Macrophage tumor necrosis factor-α (G: 5.0±1.1 ng/2×10⁶ cells·hr⁻¹; GA: 3.7±0.8 ng/2×10⁶ cells·hr⁻¹; and HP: 1.7±0.6 ng/2×10⁶ cells·hr⁻¹; p.05 G vs. HP) and nitric oxide (G: 4.5±1.1 ng/2×10⁶ cells·hr⁻¹; GA: 5.1±1.0 ng/2×10⁶ cells·hr⁻¹; and HP: 1.0±0.5 nmol/2×10⁶ cells·hr⁻¹; p.05 G and GA vs. HP) productions were higher in the G and GA groups compared to the HP group. Macrophages from the G and GA groups exhibited increased arginine consumption.In diabetic obese and endotoxemic rats, a diabetes-specific formula leads to a lower mortality, a decreased insulin resistance, and an improvement in peritoneal macrophage function. Arginine supplementation has no additional effect. These data support the use of such disease-specific diets in critically ill diabetic and obese patients.

We read with interest the recent article by Adam et al. (1) suggesting an action of metformin on citrulline metabolism in patients with type 2 diabetes. This study provides compelling evidence that metformin treatment is associated with a decrease in plasma citrulline in these patients and also in multiple tissues in diabetic mice. The authors speculate that high citrulline may be associated with insulin resistance, and the accompanying commentary (2) questioned whether a metformin-mediated decrease in citrullinemia may be involved in metformin’s mechanism of action. We would like to draw attention on some aspects of citrulline’s properties. First, in terms of citrulline concentration, the study by Adam et al. (1 …

PURPOSE OF REVIEW The gut microbiota is a very complex ecosystem which interacts extensively with the host, influencing multiple metabolic and physiological functions. Several diseases have been shown to be associated with specific alterations in gut microbiota. It is more and more underscored as playing a major role in the development of insulin resistance and inflammation associated with excess weight gain. RECENT FINDINGS Recent studies in obese patients have shown perturbations in gut microbiota with a weight gain-associated increase in the Firmicutes/Bacteroidetes ratio ameliorated by various attempts at inducing weight loss. SUMMARY Intestinal microbiota may contribute to the development of inflammation and insulin resistance by two main mechanisms. First, gut microbiota might facilitate energy harvest from the gut leading via perturbation in energy homeostasis to fat deposition and increased adipokine production and plasma free fatty acid levels both contributing to insulin resistance and inflammation. Alternatively, it can initiate an inflammatory process either originating from the intestine or generated at the peripheral level via endotoxin leakage into the blood from the intestine, both leading secondarily to insulin resistance.

summary Citrulline (CIT) is synthesized from arginine (ARG) and glutamine in enterocytes and metabolized by the kidneys into arginine, which is available for peripheral tissues. Thus CIT, rather than ARG, could be a limiting amino acid (AA) in situations of intestinal failure. This was verified in a rat model of short bowel syndrome. The effects of CIT were further tested in renutrition of malnourished rats and in healthy volunteers fed a hypoproteic diet. CIT supplementation improved protein synthesis (PS) and ARG availability more than ARG itself, which is explained by the fact that CIT, unlike ARG, is very efficiently transported into enterocytes and escapes hepatic uptake. Action of CIT on PS is mediated through the mTOR pathway. A key issue is why CIT should stimulate PS. CIT could be a counterpart of leucine, with leucine stimulating PS in the postprandial state, while CIT acts when protein intake is low or nil to maintain PS at a minimal level compatible with life. CIT could also be a safe way to deliver ARG to endothelial and immune cells, and can certainly prevent excessive uncontrolled nitric oxide production.

Recent publications highlight a frequent loss of muscle mass in chronic liver diseases, including nonalcoholic fatty liver disease (NAFLD), and its association with a poorer prognosis. In NAFLD, given the role of muscle in energy metabolism, muscle loss promotes disease progression. However, liver damage may be directly responsible of this muscle loss. Indeed, muscle homeostasis depends on the balance between peripheral availability and action of anabolic effectors and catabolic signals. Moreover, insulin resistance of protein metabolism only partially explains muscle loss during NAFLD. Interestingly, some data indicate specific alterations in the liver–muscle axis, particularly in situations such as excess fructose/sucrose consumption, associated with increased hepatic de novo lipogenesis (DNL) and endoplasmic reticulum stress. In this context, the liver will be responsible for a decrease in the peripheral availability of anabolic factors such as hormones and amino acids, and for the production of catabolic effectors such as various hepatokines, methylglyoxal, and uric acid. A better understanding of these liver–muscle interactions could open new therapeutic opportunities for the management of NAFLD patients.

Background: Immune evasion and deregulation of energy metabolism play a pivotal role in cancer progression. Immunosuppression in the tumor microenvironment can be based on the mutual metabolic requirements of immune and tumor cells. We evaluated the value of resting energy expenditure (REE) as a predictor of outcome, in mNSCLC patients under Nivolumab, an immune checkpoint inhibitor. Methods: We studied the relation between REE, clinical and biological markers of cachexia and inflammation, and response to Nivolumab in 82 consecutive mNSCLC patients. Efficacy was assessed every 2 months according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. REE was measured using indirect calorimetry, before the initiation of Nivolumab. According to their REE and with the use of Boothby's standard, patients were categorized as hypermetabolic, normometabolic and hypometabolic. Body mass index (BMI), performance status (PS), C-reactive protein (CRP), albumin, Neutrophil Lymphocyte R Ratio (NLR) and PD-L1 tumor expression were also recorded. Results: Patients characteristics were: 62% males, median age of 65 years (range 37-78), 61% PS 0-1, median BMI of 24 kg.m-² (range 17-39), 78% nonsquamous NSCLC. The analysis of REE was available for 69 out of 82 consecutive pts: 37.7% were hypermetabolic, 47.8% were normometabolic, and 14.5% were hypometabolic. In univariate analysis, hypometabolism was a strong predictive marker of disease progression (Table 1), with positive and negative predictive values of 0.80 and 0.52 respectively. In multivariate analysis, independent parameters associated with disease progression were baseline hypometabolism (vs normometabolism: OR 1.77 [1.31-2.39] p= 0.0004) and albumin (per 1pt increase: OR 0.96 [0.94-0.99] p= 0.005). Conclusion: Rest energy expenditure assessed by calorimetry appears as a biomarker of nivolumab clinical activity independently of PD1/PDL1 status. Table 1Disease control (best response) n (%)115% calculated REE n=26 (37.7%) Hypermetabolicunivariate OR (Hypometabolic vs normometabolic)pProgression8 (80%)11 (33%)17 (65%)8 [1.4-44.2]0.0007Disease control rate2 (20%)22 (67%)9 (35%) Citation Format: Claire Gervais, Pascaline Boudou-Rouquette, Anne Jouinot, Jeanne Chapron, Jennifer Arrondeau, Marco Alifano, Frédérique Giraud, Olivier Huillard, Jérôme Alexandre, Clara Vazeille, Jean-Philippe Durand, Karen Leroy, Marie-Pierre Revel, Jean-Pascal de Bandt, Luc Cynober, Diane Damotte, Audrey Lupo-Mansuet, François Goldwasser. Prediction of the efficacy of nivolumab using resting energy expenditure in metastatic non-small cell lung cancer (mNSCLC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1693.

BACKGROUND: We previously confirmed in humans the existence of a pathway of glutamine into citrulline and arginine, which is preferentially stimulated by luminally provided glutamine. However, because glutamine is unstable, we tested this pathway with a stable dipeptide of glutamine. OBJECTIVES: The objectives were to explore whether alanyl-glutamine contributes to the synthesis of arginine in humans and whether this depends on the route of administration. DESIGN: The study was conducted under postabsorptive conditions during surgery. Sixteen patients received alanyl-[2-(15)N]glutamine enterally or intravenously together with intravenously administered stable-isotope tracers of citrulline and arginine. Blood was collected from an artery, the portal vein, a hepatic vein, and the right renal vein. Arterial and venous enrichments and (tracer) net balances of alanyl-glutamine and glutamine, citrulline, and arginine across the portal drained viscera, liver, and kidneys were determined. Parametric tests were used to test results (mean +/- SEM). P < 0.05 was considered significant. RESULTS: Twice as much exogenous glutamine was used for the synthesis of citrulline when alanyl-glutamine was provided enterally (5.9 +/- 0.6%) than when provided intravenously (2.8 +/- 0.3%) (P < 0.01). Consequently, twice as much exogenous glutamine was used for the synthesis of arginine when alanyl-glutamine was provided enterally (5 +/- 0.7%) than when provided intravenously (2.4 +/- 0.2%) (P < 0.01). However, results at the organ level did not explain the differences due to route of administration. CONCLUSIONS: Alanyl-glutamine contributes to the de novo synthesis of arginine, especially when provided enterally. A stable-isotope study using a therapeutic dose of alanyl-glutamine is needed to investigate the clinical implications of this finding.

Glutamine and vitamin E may prevent hepatic ischemia-reperfusion (I/R) injuries. Our aim was to investigate the effects of glutamine, either alone or combined with vitamin E, against I/R in the isolated perfused rat liver.Four groups of 8 livers from male Sprague-Dawley rats were isolated and submitted to a 45-min no-flow ischemia and reperfusion in the presence of alanine 2 mM, alanine 2 mM plus vitamin E 150 microM, Alanyl-Glutamine (AlaGln) 2 mM, or AlaGln 2 mM plus vitamin E 150 microM. Six non-perfused livers were studied in parallel. Liver function, metabolic parameters, oxidative stress and inflammatory parameters have been studied.AlaGln was rapidly cleared from the perfusate (436+/-41 nmol min(-1) g(-1)) and lowered transaminase release during reperfusion (ALT: -59%), significantly so in the AlaGln+Vit E group (ALT: -65%, p0.05). The association of glutamine with vitamin E led to lower degrees NO (-83%, p0.05) production, better preserved hepatic glutathione content and, as with vitamin E alone, preserved hepatic vitamin A and significantly decreased malondialdehyde (-85%, p0.05).Both glutamine, by attenuating inflammatory response, and vitamin E, via its antioxidative properties, showed complementary protective effects against I/R-induced hepatic injury. These data emphasize the potential benefit of combining glutamine and vitamin E supplementation in hepatic I/R injury.