Intestinal and hepatic metabolism of glutamine and citrulline in humans

Abstract

Glutamine plays an important role in nitrogen homeostasis and intestinal substrate supply. It has been suggested that glutamine is a precursor for arginine through an intestinal-renal pathway involving inter-organ transport of citrulline. The importance of intestinal glutamine metabolism for endogenous arginine synthesis in humans, however, has remained unaddressed. The aim of this study was to investigate the intestinal conversion of glutamine to citrulline and the effect of the liver on splanchnic citrulline metabolism in humans. Eight patients undergoing upper gastrointestinal surgery received a primed continuous intravenous infusion of [2-(15)N]glutamine and [ureido-(13)C-(2)H(2)]citrulline. Arterial, portal venous and hepatic venous blood were sampled and portal and hepatic blood flows were measured. Organ specific amino acid uptake (disposal), production and net balance, as well as whole body rates of plasma appearance were calculated according to established methods. The intestines consumed glutamine at a rate that was dependent on glutamine supply. Approximately 13% of glutamine taken up by the intestines was converted to citrulline. Quantitatively glutamine was the only important precursor for intestinal citrulline release. Both glutamine and citrulline were consumed and produced by the liver, but net hepatic flux of both amino acids was not significantly different from zero. Plasma glutamine was the precursor of 80% of plasma citrulline and plasma citrulline in turn was the precursor of 10% of plasma arginine. In conclusion, glutamine is an important precursor for the synthesis of arginine after intestinal conversion to citrulline in humans.

Figure 1. Eight patients undergoing upper gastrointestinal surgery received a primed, continuous intravenous infusion of [2-¹⁵N]glutamine (A) and [ureido-¹³C–²H₂]citrulline (B)

Within 30 min an isotopic steady state was achieved for both administered tracers. During the experiment significant enrichments of isotopically labelled end products [¹⁵N]citrulline (A) and [¹³C–²H₂]arginine (B) occurred. The ratio between product enrichment and precursor enrichment represents the contribution of the precursor to whole body plasma rate of appearance of the product according to eqn (2).

Figure 2. Portal drained viscera glutamine metabolism in eight patients undergoing upper gastrointestinal surgery

The PDV disposed glutamine from the circulation (P = 0.004 versus zero) and simultaneously tended to produce glutamine and release it into the portal vein (P = 0.07 versus zero). Glutamine net flux and PDV glutamine-to-citrulline conversion were both significantly different from zero (P = 0.0003 and P = 0.013, respectively). Thirteen per cent of intestinal glutamine uptake was used for citrulline production.

Figure 3. Fractional extraction of glutamine by the portal drained viscera in eight patients undergoing upper gastrointestinal surgery

[¹⁵N]Glutamine uptake, representing unidirectional glutamine disposal, was related to [¹⁵N]glutamine influx, evidencing that PDV glutamine disposal is related to PDV glutamine influx. PDV net flux, which is the resultant of PDV glutamine disposal and production, is not related to glutamine influx (inset).

Figure 4. Citrulline metabolism by the portal drained viscera in eight patients undergoing upper gastrointestinal surgery

No PDV citrulline disposal was found, whereas the PDV released citrulline into the portal vein (production and net flux both P < 0.005 versus zero). Quantitatively glutamine was the only important precursor for PDV citrulline production.

Figure 5. Splanchnic (A) and hepatic (B) glutamine metabolism in eight patients undergoing upper gastrointestinal surgery

The splanchnic area simultaneously disposed and produced glutamine, leading to net glutamine consumption (all P < 0.02 versus zero). Splanchnic glutamine net flux was determined by PDV glutamine net flux. The liver simultaneously disposed and released large amounts of glutamine (both P < 0.02), resulting in a zero net balance.

Figure 6. Splanchnic (A) and hepatic (B) citrulline metabolism in eight patients undergoing upper gastrointestinal surgery

The splanchnic area tended to simultaneously dispose of and produce citrulline (P = 0.085 and P = 0.014 versus zero, respectively). Net splanchnic citrulline flux (P = 0.027 versus zero) was determined by PDV net flux. The liver disposed a considerable amount of citrulline (P = 0.039 versus zero). However, both hepatic citrulline production and hepatic net flux failed to reach statistical significance.