International Journal of Prevention and Treatment

p-ISSN: 2167-728X    e-ISSN: 2167-7298

2015;  4(2): 34-39

doi:10.5923/j.ijpt.20150402.03

Therapeutic Targets of Glutamine in Parenteral Nutrition: A Medical Science Review

Alberto Leguina-Ruzzi

Hematology and Oncology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile

Correspondence to: Alberto Leguina-Ruzzi , Hematology and Oncology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.

Email:

Copyright © 2015 Scientific & Academic Publishing. All Rights Reserved.

Abstract

Glutamine is the most abundant free amino acid with multiple biological functions. Under hypercatabolic conditions, its levels are considerably depleted a condition that correlates with pathological severity and has been suggested as an independent predictor of mortality in intensive care unit patients. The supplementation of this amino acid to parenteral nutrition has been widely used for the management of intensive care complication. However, controversial clinical reports have generated reluctance in the use of this pharmaco-nutrient. In this review, we address the molecular aspects of the reported beneficial effects of glutamine. From a basic science point of view considering in vitro, ex vivo and in vivo studies, the evidence describes various metabolic pathways in which glutamine plays beneficial roles. These pathways support the role of glutamine as an antioxidant, detoxicant, heat shock protein inductor, immune enhancer, nitrogen stabilizer and insulin sensitizer. We strongly believe that there is a mandatory need for more clinical trials, which could address the clinical concerns of glutamine supplementation to parenteral nutrition. However, from the molecular point of view and based on the current clinical studies, the use of glutamine is still a clinical and economically attractive management strategy.

Keywords: Glutamine, Parenteral Nutrition, Pharmaco-nutrient

Cite this paper: Alberto Leguina-Ruzzi , Therapeutic Targets of Glutamine in Parenteral Nutrition: A Medical Science Review, International Journal of Prevention and Treatment, Vol. 4 No. 2, 2015, pp. 34-39. doi: 10.5923/j.ijpt.20150402.03.

Article Outline

1. Introduction
2. Molecular Targets of Glutamine
    2.1. Glutathione Biosynthesis
    2.2. Heat Shock Proteins
    2.3. Bacterial Translocation
    2.4. Lymphocytic Function
    2.5. Nitrogen Balance
    2.6. Insulin Sensitivity
3. When not to Use Glutamine?
4. Conclusions
ACKNOWLEDGEMENTS

1. Introduction

Glutamine (Gln) is the most abundant free amino acid (AA) in the body with concentrations fluctuating around 500-900 µmol/L [1]. The biological functions of this AA have been widely studied, opening a whole new world of targets in which Gln could modulate physiological functions such as immune enhancer, muscular maintainer, nitrogen transporter, neuronal mediator, pH homeostasis, gluconeogenesis, aminosugar synthesis, among others [2].
For decades it has been used as a supplement of total parenteral nutrition (TPN) in its dipeptide Alanylglutamine form, because of its limited solubility and instability in aqueous solution [3].
In 1990 it was identified that Gln is one of the only conditionally essential AA, meaning that in hypercatabolic or stress conditions the body suffers depletion in the circulating levels [4]. This characteristic confers the option of Gln use as a pharmaco-nutrient, meaning that through its targets it could improve the outcome of patients that are suffering a hypercatabolic or hypermetabolic condition.
Studies have identified the patients in whom a depletion of Gln is correlated with severity of their pathological condition [5]. Furthermore, this phenomenon is an independent predictor of mortality in intensive care unit (ICU) patients [6].
A series of clinical trials, meta-analyses and systematic reviews have shown that supplementation of TPN with Gln improves three major clinical outcomes: 1) mortality, 2) infections, 3) length of stay (LOS) and 4) cost effectiveness [7-9].
Even though nutrition guidelines recommend its use in ICU patients with TPN requirement (Table 1), controversy has emerged after the publication of the REDOX study [10] causing distrust and fear in the use of this supplement.
Table 1. International Guidelines for Glutamine Supplementation
     
In this review we summarize the evidence provided by the basic science research that supports the beneficial effects of supplementation with Gln in main ICU patients outcomes. The literature searching was made in pubmed following the queries “glutamine” combined with “supplementation”, “parenteral nutrition”, “ICU” and/or “pharmaconutrient”. Reports in English and from the last 3 decades were considered for this purpose.

2. Molecular Targets of Glutamine

2.1. Glutathione Biosynthesis

Glutathione (GSSH) is a reduced non-protein thiol, which is present in all mammalian tissues and has important antioxidant and detoxification functions [15]. Gln is a precursor of GSSH when associated with cysteine in the cytoplasmic compartment of the cell [16]. This reduced metabolite has strong affinity to free radicals and toxins, passing to oxidized glutathione disulphide (GSSG). GSSG can be converted again to GSSH or be translocated to the vacuole for degradation, conferring its beneficial capacities to the cells as shown in Figure 1 [17].
Figure 1. Glutathione antioxidant and detoxicant intracellular capacity

2.2. Heat Shock Proteins

Heat shock proteins (HSP) (also known as stress response proteins) are highly conserved and present in all cells [18]. An important part of these molecules participate in protein folding, assembly and correct transport, enabling them to act as cytoprotective molecules [19]. It has been shown that in sepsis or in inflammatory response syndrome, there is a significant reduction in the intracellular levels of HSP72, which correlates with severity of illness and mortality [20].
Hamiel et al. showed that Gln enhanced the HSP70 expression through the crosstalk with the hexosamine pathway [21]. Interestingly this process could ameliorate cell stress and protect cellular integrity, which in turn potentiates the regeneration.
Figure 2. Enhancement of HSP synthesis by Gln and hexosamine cross talk

2.3. Bacterial Translocation

This pathological condition is based in the passage of viable bacteria from the gastrointestinal tract to extrainstestinal sites, giving rise to a systemic infective condition [22].
ICU patients are at higher risk of bacterial translocation (BT), 15% of the ICU population is affected, particularly those with intestinal damage. This condition is one of the main causes of sepsis and multiorganic failure [23].
Interestingly, it has been reported that the supplementation of Gln to the TPN reduces the prevalence of BT and prevents inflammatory intestinal complications [24]. In vivo and in vitro studies have reported that the enterocyte uses Gln as its principal energy source [25], enhancing its growth and proliferation [26]. Moreover, the enterocyte is capable of transporting it to and from the intestinal circulation, creating a bidirectional supply of this AA [27]. This process uses a series of antiporters coupled to Na+ and H+ from the family ASCT2 [28]. On the other hand, a deprivation of this AA induces BT, which suggests the importance of Gln in the intestinal barrier integrity [29]. This suggests a protective role for Gln in intestinal integrity, providing fuel for the enterocyte and therefore as a preventive mechanism of sepsis.
Figure 3. Glutamine transport and metabolism in the enterocyte

2.4. Lymphocytic Function

The activation of naïve T cells is a pivotal process for the immune response and is a highly energetic event that requires an increase in nutrient metabolism [30]. Among the processes required, Gln uptake is regulated by the ERK/MAPK pathway and is fundamental for the activation of this cell type. See Figure 4. The Gln AA also modulates the proliferation of the Naive T cells [31-32]. In vitro studies have shown that extracellular Gln is essential as a respiratory fuel and not only has an impact on the lymphocyte, but also mediates the macrophage phagocytic and secretory function as well as the neutrophil bacterial killing [33]. In vivo studies have suggested that Gln in close interaction with glucose metabolism might be potential targets for the anti-inflammatory and immunomodulation effect of physical activity, which could be particularly relevant for patients with reduced mobility [34].
In relation to the inmunomodulatory effect of Gln, a clinical study showed that its supplementation significantly decreased nosocomical and bloodstream infections after surgery, suggesting a positive impact on surgical intensive care [35].
Figure 4. Metabolic processes required for lymphocyte activation

2.5. Nitrogen Balance

The nitrogen balance (NB), measured as nitrogen input minus output, was the first approach used to study the utilization of nitrogen in the body. Even though this method has several limitations, it is still widely use in clinic [36].
The regulation of a relatively constant level of adult body protein is a physiologically favourable process to maintain the cellular integrity [37]. It is widely accepted that ICU patients with TPN present a negative NB that correlates with the clinical outcome [38-39]. Interestingly, Gln supplementation has shown the capacity to improve the NB from the third day of use [40]. Furthermore, the Gln supplemented diet did not affect portal ammonia concentration, showing that it does not affect the excretion pathway [41].

2.6. Insulin Sensitivity

Hyperglycaemic crises are metabolic emergencies commonly associated with uncontrolled diabetes mellitus, which may result in significant morbidity or death [42]. This complication is also common in critical illness, regardless of a diabetes history. The prevalence in UCI patients is around 40% [43] and classically was presumed to be an adaptive response to stress [44]. However, more recent reports have shown that hyperglycemia is associated with increased mortality and morbidity [45]. Guidelines for glycemic control have been suggested by the main organizations giving specific goals as shown in table 2.
Table 2. Guidelines for Glucose Blood Levels in Critically Ill Patients
     
The role of Gln in insulin sensitivity has been widely studied [49]. A recent randomized-controlled clinical trial demonstrated that the supplementation of Gln to the TPN for more than 7 days reduces significantly the hyperglycemic episodes and the insulin requirement in ICU polytrauma patients [50]. In vivo studies have demonstrated the Gln stimulates calcium dependent insulin secretion and beta-cell depolarization [51]. In vitro, it has been shown that Gln enhances the insulin glucose response. The process involves the metabolism of the gamma-glutamyl cycle, the glutathione synthesis and the mitochondrial function as shown in Figure 5 [52].
Figure 5. Metabolic pathway in insulin release potentiation by Gln

3. When not to Use Glutamine?

Although Gln as a molecule seems promising for treatment of ICU patients, it is fundamental to identify when not to use it. Ironically, the biggest Gln clinical that opened the “can of worms” provided the most valuable information. The REDOX study reported that Gln did not confer any beneficial effect and increased mortality [10]. This conclusion was mainly because patients fulfilling contraindication parameters were included and an inappropriate dose was used. However, the report is telling us how not to use glutamine and this information is a valuable guide for the correct use of Gln, as shown in Table 3. Additionally, a recent report that had a great impact in the current Canadian Nutrition Guide supports the idea of the proper “time-frame” of supplementation [53].
Table 3. Contraindications of Glutamine
     
Even when all of the above parameters of contraindication are equally important, we gave a greater impact to the kidney and liver function. It is important to recognize the cytotoxic effect of Gln. In vitro related species can participate in pathways that lead to apoptosis [54].
That is why the proper excretion of Gln is required for safety of patients. In the first step, in the kidney the AA passes through a metabolic transformation producing urea that is excreted by the kidney. Additionally, the kidney can metabolize Gln in a process called glutaminolysis. In a series of biochemical reactions the Gln is lysed to glutamate, aspartate, CO2, pyruvate, lactate, alanine and citrate. See figure 6 [55].
Figure 6. Liver and kidney glutamine excretion through ureagenesis and glutaminolysis

4. Conclusions

Strong evidence emerges from the basic science showing the beneficial effects of Gln in the metabolism. Interestingly, in vitro is used in classical media ranges from 500 to 2000 µmol/L depending on the cell culture requirement, values that could represent a physiological state and AA supplementation. Gln pleiotropic functions make it a great candidate for the treatment of hypercatabolic conditions. However, important lessons have to be learned from the controversial evidence that impacts negatively on Gln use. The correct identification of patients for whom it is safe and the correct usage of the supplement are pivotal for its safe administration.
A critical and rigorous evaluation of the clinical trials is required to avoid misunderstandings and errors in the real properties of this AA. There is an urgent need for more clinical trials that could address the concerns of Gln use in the clinical field.

ACKNOWLEDGEMENTS

No sources of funding were used to assist in preparation of this manuscript. The author acknowledges that in figure 1 a different glutamine designation was used. This was intentionally made to maintain the fidelity to the cited reference.
The author has no conflict of interests that are directly relevant to the content of this review.

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