The small intestine is not only responsible for terminal digestion and absorption of nutrients, but it also plays an important role in catabolism of arterial glutamine and dietary amino acids. Most of glutamine and almost all of glutamate and aspartate in the diet are catabolized by small intestinal mucosa, and CO2 accounts for 56-64% of their metabolized carbons. The small intestinal mucosa also plays an important role in degrading arginine, proline and branched-chain amino acids, and perhaps methionine, lysine, phenylalanine, threonine, glycine and serine in the diet, such that 30-50% of these dietary amino acids are not available to extraintestinal tissues. Dietary amino acids are major fuels for the small intestinal mucosa and are essential precursors for intestinal synthesis of glutathione, nitric oxide, polyamines, purine and pyrimidine nucleotides, and amino acids (alanine, citrulline and proline), and are obligatory for maintaining intestinal mucosal mass and integrity. Because intestinal amino acid catabolism plays an important role in modulating dietary amino acid availability to extraintestinal tissues, it has important implications for the utilization efficiency of dietary protein and amino acids in animals and humans.

Intestinal Mucosal Amino Acid Catabolism

Although it is well known that the intestinal tract has a high metabolic rate, the substrates that are used to generate the necessary energy remain poorly established, especially in fed animals. Under fed conditions, the quantification of substrate used by the gut is complicated by the fact that potential oxidative precursors are supplied from both the diet and the arterial circulation. To circumvent this problem, and to approach the question of the compounds used to generate ATP in the gut, we combined measurements of portal nutrient balance with enteral and intravenous infusions of [U- 13 C]substrates. We studied rapidly growing piglets that were consuming diets based on whole-milk proteins. The results revealed that 95% of the dietary glutamate presented to the mucosa was metabolized in first pass and that of this, 50% was metabolized to CO 2 . Dietary glucose was oxidized to a very limited extent, and arterial glutamine supplied no >15% of the CO 2 production by the portal-drained viscera. Glutamate was the single largest contributor to intestinal energy generation. The results also suggested that dietary glutamate appeared to be a specific precursor for the biosynthesis of glutathione, arginine and proline by the small intestinal mucosa. These studies imply that dietary glutamate has an important functional role in the gut. Furthermore, these functions are apparently different from those of arterial glutamine, the substrate that has received the most attention.

Intestinal Glutamate Metabolism

Metabolism and functions of L-glutamate in the epithelial cells of the small and large intestines.

Glutamate is one of the most abundant of the amino acids. In addition to its role in protein structure, it plays critical roles in nutrition, metabolism and signaling. Post-translational carboxylation of glutamyl residues increases their affinity for calcium and plays a major role in hemostasis. Glutamate is of fundamental importance to amino acid metabolism, yet the great bulk of dietary glutamate is catabolyzed within the intestine. It is necessary for the synthesis of key molecules, such as glutathione and the polyglutamated folate cofactors. It plays a major role in signaling. Within the central nervous system, glutamate is the major excitatory neurotransmitter and its product, GABA, the major inhibitory neurotransmitter. Glutamate interaction with specific taste cells in the tongue is a major component of umami taste. The finding of glutamate receptors throughout the gastrointestinal tract has opened up a new vista in glutamate function. Glutamate is truly a functional amino acid.

Glutamate: a truly functional amino acid

Metabolic fate and function of dietary glutamate in the gut

[1,2-13C2]glutamate and [ring-2H5]phenylalanine were infused for 7 h into postabsorptive healthy subjects on two occasions. The tracer infusion was by the intravenous route for 3.5 h and by the nas...

Oxidation of glutamic acid by the splanchnic bed in humans

In response to hypoglycemia, healthy individuals rapidly antagonize insulin action on glucose and lipid metabolism, but the effects on protein metabolism are unclear. Because amino acids are an important substrate for gluconeogenesis and a fuel alternative to glucose for oxidation, we evaluated whether hypoglycemia antagonizes the hypoaminoacidemic and the antiproteolytic effects of insulin and changes the de novo synthesis of glutamine, a gluconeogenic amino acid. To this purpose, in 7 healthy subjects, we performed 2 studies, 3.5 h each, at similar insulin but different glucose concentrations (i.e., 4.9 +/- 0.1 mmol/l [euglycemic clamp] or 2.9 +/- 0.2 mmol/l [hypoglycemic clamp]). As expected, hypoglycemia antagonized the insulin suppression of glucose production achieved in euglycemia (from 21 +/- 15 to 116 +/- 12% of basal, P < 0.001), the stimulation of glucose uptake (from 207 +/- 28 to 103 +/- 7% of basal, P < 0.01) and the suppression of circulating free fatty acids (from 30 +/- 5 to 80 +/- 17% of basal, P < 0.001). In contrast, hypoglycemia increased the insulin suppression of circulating leucine (from 63 +/- 1 to 46 +/- 2% of basal, P < 0.001) and phenylalanine (from 79 +/- 3 to 64 +/- 3% of basal, P < 0.001) concentrations. Hypoglycemia did not change the insulin suppression of proteolysis (from 79 +/- 2 to 82 +/- 4% of basal, P < 0.001). However, hypoglycemia doubled the insulin suppression of the glutamine concentrations (from 84 +/- 3 to 63 +/- 3% of basal, P < 0.01) in the absence of significant changes in the glutamine rate of appearance, but it also caused an imbalance between glutamine uptake and release. This study demonstrates that successful counterregulation does not affect proteolysis. Moreover, it does not increase the availability of circulating amino acids by de novo synthesis. In contrast, despite the lower concentration of circulating amino acids, hypoglycemia increases the uptake of glutamine that can be used for gluconeogenesis and as a fuel alternative to glucose.

https://diabetes.diabetesjournals.org/content/diabetes/49/9/1543.full.pdf

Effect of hypoglycemia on amino acid and protein metabolism in healthy humans.

Glucagon causes transient hyperglycemia and persistent hypoaminoacidemia, but the mechanisms of this action are unclear. To address this question, the present study measured the effects of glucagon on glucose, leucine, phenylalanine, and glutamine kinetics. Seven healthy subjects each underwent three pancreatic clamp studies (octreotide 30 ng/kg/min, insulin 0.15 mU/kg/min, and glucagon 1.4 ng/kg/min) lasting 7 hours. During the last 3.5 hours of the studies, glucagon infusion was either unchanged (study 0) or increased to 4 and 7 ng/kg/min (studies 1 and 2). The higher glucagon infusion rates increased the glucagon concentration by 50% and 100%, respectively. [6,6-(2)H2]glucose, [2-(15)N]glutamine, 2H5-phenylalanine, and 2H3-leucine were infused to quantify the respective fluxes. Glucagon transiently increased glucose concentrations by stimulating glucose production, which peaked in 15 minutes to 3.82 +/- 0.36 and 4.21 +/- 0.33 mg/kg/min in studies 1 and 2 and then returned to the postabsorptive levels. Glucagon decreased the glutamine concentration (-10% +/- 2% and -22% +/- 2% in studies 1 and 2 v study 0, P < .05), because glutamine uptake became greater than glutamine release (balance from -1.9 +/- 0.9 in study 0 to -8.1 +/- 1.1 and -13.6 +/- 1.0 micromol/kg/h in studies 1 and 2, P < .01). Glucagon decreased the leucine concentration (-11% +/- 3% in study 2 v study 0, P < .02) and caused a small increment in proteolysis (+6% in study 2 v study 0, P < .01) that was related to the decrement in glutamine concentrations. Phenylalanine kinetics were not significantly affected. These results show that glucagon promotes the uptake of gluconeogenic substrates but does not increase their release, suggesting that glucagon-induced hyperglycemia is short-lived because glucagon fails to provide more fuel for gluconeogenesis. The small increase in proteolysis and the depletion of circulating glutamine prove that physiologic hyperglucagonemia can contribute to protein catabolism.

Glucagon increases glutamine uptake without affecting glutamine release in humans

The branched-chain ketoacids (BCKAs) are used as dietary supplements to spare essential amino acid nitrogen, yet little is known about their absorption and utilization in the body. To study the fate of enterally delivered α-ketoisocaproate (KIC), seven healthy adults were infused in the postabsorptive state with [1- 13 C]KIC and [phenyl- 2 H 5 ]phenylalanine intravenously (NGI) and with [5,5,5- 2 H 3 ]KIC by nasogastric tube (NG). After 3.5 hours, the routes of tracer infusion were switched for an additional 3.5 hours. Each subject received a second infusion study on a different day with the order of tracer infusion reversed. KIC and phenylalanine kinetics and first-pass uptake and disposal of the enteral tracer by the splanchnic bed were calculated from the tracer enrichments measured in plasma KIC, leucine, and phenylalanine and breath CO 2 . Phenylalanine flux was 39.5 ± 1.2 μmol/kg/h during the IV infusion periods. KIC flux was 33.1 ± 1.8 and 30.4 ± 1.4 μmol/kg/h measured with 13 C- and 2 H 3 -KIC, respectively, and these values were significantly different. The fraction of enterally delivered tracer sequestered by the splanchnic bed on the first pass was 30.9% ± 2.0%, 30.0% ± 1.4%, and 30.7% ± 2.7% for 13 C-KIC, 2 H 3 -KIC, and 2 H 5 -phenylalanine, respectively. The fraction of infused 13 C-KIC tracer recovered as 13 CO 2 was 27.1% ± 1.2% and 24.0% ± 0.9% during IV and NG infusion, respectively. From these data, the fraction of ng KIC tracer extracted and oxidized on the first pass was calculated to be 5.1% ± 1.1%. This fraction was greater than that previously reported for leucine extraction and oxidation (2%), but it was still only a small fraction of the overall extraction ( 5 30 = 16%). Because the only two fates of the KIC tracer extracted by the splanchnic bed are oxidation or transamination to leucine, the majority (84%) of the KIC tracer was extracted and converted to leucine. These results demonstrate that KIC delivered enterally to postabsorptive humans is rapidly extracted and predominantly converted to leucine by the splanchnic bed. This leucine appears to be available for use by both the splanchnic bed and the whole body.

Splanchnic bed utilization of enteral α-ketoisocaproate in humans

Erratum: The effects of maintenance doses of FK506 versus cyclosporin A on glucose and lipid metabolism after orthotopic liver transplantation (Transplantation (November 27, 1999) 68:10 (1532-1541))

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