Glycylglutamine: Metabolism and Effects on Organ Balances of Amino Acids in Postabsorptive and Starved Subjects H. LOCHS, W. HUBL, S. GASIC, ET AL. American Journal of Physiology 262 (Endocrinology and Metabolism 25): E155‐E160, 1992

The aims of this study were: (1) to investigate the effect of an intravenous infusion of the dipeptide glycylglutamine on organ fluxes of amino acids in postabsorptive and briefly starved human subjects and (2) to investigate the effect of starvation on the metabolism of glycylglutamine. Studies were carried out on 17 male subjects who were matched for age and weight. The postabsorptive group (N = 8) was fasted overnight (12 to 14 hours), whereas the briefly starved group (N = 9) was fasted for 84 to 86 hours before the experiment. On the day of the experiment, all subjects underwent catheterization of the hepatic, renal, right femoral, and antecubital veins and the right and left femoral arteries. During a 30‐minute equilibration period, primed, constant infusions of indocyanine green dye and p‐aminohippurate were begun to assess hepatic, muscle (right lower extremity), and renal plasma flow. After a 45‐minute saline infusion control period, the dipeptide glycylglutamine (100 μmol/kg per hour) was infused during a 120‐minute experimental period. Blood was sampled every 15 minutes during the study, and plasma concentrations of the dipeptide and individual amino acids were determined. At the end of each experiment, urine was collected for dipeptide and amino acid analysis. The arterial concentration of glycylglutamine reached a steady‐state level after 60 minutes of infusion. Amino acid and dipeptide balances across organs were calculated as the product of the arterial‐venous concentration differences and the respective plasma flow. A negative balance indicated net release; a positive balance indicated net uptake. The arterial concentrations of glycylglutamine during the experimental period were similar in both postabsorptive and starved subjects (265 ± 18 and 241 ± 13 μmol/ L, respectively). The infusion of glycylglutamine resulted in significantly increased arterial concentrations of glycine and glutamine in both postoperative and starved subjects. Less than 1% of the glycylglutamine infused into postabsorptive and starved subjects was recovered in urine. Starvation had no effect on organ plasma flow to the lower extremity, kidney, or splanchnic bed. Starvation decreased renal clearance of glycylglutamine approximately 45% us the postabsorptive group but did not have an effect on muscle and splanchnic tissue clearance. Focusing on the lower extremity (muscle bed), the infusion of glycylglutamine in the postabsorptive patient abolished net glycine release (—6 ± 2 to 3 ± 2 μmol/min) and increased net uptake of serine (3 ± 0.4 to 5 ± 0.9 μmol/min). Infusion in the starved patient decreased net muscle release of glutamine, glycine, alanine, and serine (‐17 ± 2 to ‐12 ± 2, ‐7 ± 1 to ‐3 ± 0.4, ‐27 ± 3 to ‐23 ± 2, and ‐3 ± 0.7 to ‐2 ± 0.4 μmol/min, respectively) compared with the saline control period. Focusing on the kidney, starvation increased net uptake of glutamine (41 ± 5 to 79 ± 1 μmol/min) and increased net production of glutamate (‐18 ± 3 to ‐32 ± 5 μmol/min). The infusion of glycylglutamine in starved subjects significantly decreased net glutamine uptake (‐79 ± 1 to 17 ± 9 μmol/min) in the kidney, which became a net producer of glycine (5 ± 4 to ‐30 ± 4 μmol/min). Focusing on the splanchnic bed, starvation significantly increased net uptake of glycine, serine, threonine, methionine, isoleucine, and leucine and increased net splanchnic release of glutamate. In'the postabsorptive subject, the infusion of glycylglutamine markedly increased the net uptake of glutamine and glycine (71 ± 9 to 141 ± 16 and 16 ± 5 to 33 ± 5 μmol/min, respectively). There was a similar trend in starved patients, although the magnitude of the change was less. During starvation, net alanine uptake did not increase significantly (104 ± 18 to 132 ± 12 μmol/ min), and the infusion of glycylglutamine did not affect net alanine uptake. The infusion did increase net uptake of serine and threonine in the postabsorptive subject (22 ± 4 to 31 ± 5 and 14 ± 2 to 19 ± 2 μmol/min, respectively) but had no similar effect on the starved subject.