Alterations in glutamine metabolism and its conversion to citrulline in sepsis

Abstract

Alterations in glutamine metabolism and its conversion to citrulline in sepsis. Am J Physiol Endocrinol Metab 304: E1359 -E1364, 2013. First published April 23, 2013 doi:10.1152/ajpendo.00628.2012.-In enterocytes, glutamine serves as the major source of energy; another metabolic fate of glutamine is conversion to citrulline. Because sepsis can affect gut function and integrity, alterations in glutamine metabolism may exist and lead to decreased citrulline production. This study aimed to investigate how sepsis affects glutamine metabolism, including its conversion to citrulline, by measuring glutamine and citrulline flux, fractional splanchnic extraction of glutamine and leucine, and the contribution of glutamine nitrogen to citrulline in septic patients and healthy controls. Eight patients with severe sepsis and 10 healthy controls were given primed, constant intravenous infusion of [ 2 H2]citrulline and sequential administration of intravenous and enteral [␣-15 N]glutamine and [ 13 C]leucine in the postabsorptive state. The results showed that, compared with healthy controls, septic patients had a significantly lower whole body citrulline flux and plasma concentration, higher endogenous leucine flux, and higher glutamine clearance. Fractional splanchnic extraction of leucine was higher in septic patients than in controls, but fractional extraction of glutamine was not different. The majority of the 15 N label transferred from glutamine to citrulline was found at the ␣-position. These results demonstrate that lower glutamine plasma concentrations in sepsis were a result of increased glutamine clearance. Despite adequate splanchnic uptake of glutamine, there is decreased production of citrulline, suggesting a defect in the metabolic conversion of glutamine to citrulline, decreased uptake of glutamine by the enterocyte but increased uptake by the liver, and/or shunting of glutamine to other metabolic pathways. severe sepsis; stable isotopes; enterocyte THE GUT IS BELIEVED TO PLAY an important role in sepsis. In fact, it has been postulated that the gut can initiate, perpetuate, or exacerbate the systemic inflammatory response syndrome (SIRS) and lead to the development of multiorgan dysfunction syndrome (MODS) (29). Sepsis can affect gut function and mucosal integrity via a variety of mechanisms, including ischemia-reperfusion injury, mitochondrial dysfunction, and increased intestinal permeability (9). Because maintenance of gut mucosal integrity depends almost exclusively on an adequate enteral supply of amino acids both as primary source of fuel and as substrate for protein synthesis, more information is needed about the metabolic fates of enterally administered amino acids in sepsis.In health, the gastrointestinal tract is the major organ of glutamine utilization (32). Glutamine is the major source of energy for proliferating enterocytes, providing energy for ATP-dependent processes, including rapid intracellular protein turnover and nutrient transport (39). Adult rat enterocytes extract 25-33% of arterial g...

Physiological regulation of the heat shock response by glutamine: implications for chronic low-grade inflammatory diseases in age-related conditions

“…The availability of glutamine is thought to be a major factor during critical illnesses, such as sepsis, extensive burns, pancreatitis, trauma, and surgery [209,293,294]. Moreover, the concentration of glutamine in patients diagnosed with T2DM has shown a significant reduction (20 %), when compared with healthy individuals [295].…”

Combined Enteral and Parenteral Glutamine Supplementation in Endotoxemic Swine: Effects on Portal and Systemic Circulation Levels

“…In catabolic states an increased release of glutamine (GLN) from the skeletal muscle to meet the increasing demands of peripheral tissue is observed as part of the body’s conserved evolutionary response to stress, progressively leading to a depletion of GLN, proportional to the severity and duration of illness [1-3]. …”

“…Various studies in endotoxemia/sepsis models [3, 4] have reported the depletion of GLN and its consequences on body homeostasis and progress of disease. However, it has not been fully elucidated whether parenteral or enteral administration may be more beneficial in restoring GLN stores – in the same model – as, to the best of our knowledge, there are no studies regarding the effect of exogenous GLN administration on plasma levels and, especially, relating to the route of administration.…”

Interrelationships between glutamine and citrulline metabolism

“…Thus many different precursors can contribute to the synthesis of citrulline. In fact glutamine has been reported to be the main precursor in humans and mice [2,27]; proline, in infants [28,29] and neonatal pigs [30]; and arginine, in mice [31,32]. Although species differences may exist the following methodological issues have fueled the controversy regarding what precursors are used for citrulline synthesis: 1) the choice of tracer, 2) the mathematical model to interpret the isotope data, and 3) the developmental stage of the subjects or animals studied (neonate vs. adult).…”

“…[2- 15 N] (amino) glutamine has been used extensively to determine precursor-product relationship between glutamine and citrulline [2,16,27]. The limitation of the 15 N tracer is that it can label any of the three nitrogen atoms of citrulline [33▪▪].…”