489 seen in other reports.’ The authors only used definitions of diarrhea that depend on the frequency and consistency of stools and did not use measurements of stool weights or volumes. Addition of these quantitative data should provide a more accurate definition of the severity of diarrhea. It would also avoid mistaking incontinence, with multiple small stools, for diarrhea and would thus make it possible to evaluate the severity of diarrhea in patients with rectal pouches and tubes. Diarrhea is commonly seen in tube-fed patients. An important issue that needs to be resolved is the determination of the cause(s) of diarrhea in tube-fed patients. There is growing evidence that many cases of diarrhea in tube-fed patients are caused by factors other than the tube feeding itself, eg, concurrently administered medications.2,3 Establishing uniform guidelines and definitions to quantitate the degree and severity of diarrhea is necessary, but does not address the actual causes of diarrhea. Further work in this area is needed to refine and improve currently used descriptive and subjective criteria for describing and quantitating diarrhea.
comparable with that
DOUGLAS C. HEIMBURGER, MD Departments of Nutrition Sciences and Medicine University of Alabama at Birmingham Birmingham, Alabama REFERENCES 1.
2.
Kelly TWJ, Patrick MR, Hillman KM: Study of diarrhea in critically ill patients. Crit Care Med 11:7-9, 1983 Edes TE, Walk BE, Austin JL: Diarrhea in tube-fed patients: Feeding formula not necessarily the cause. Am J Med 88:91-93, 1990
3.
Heimburger DC, Sockwell DG, Geels WJ. diarrhea? Am J Clin Nutr 53:P-19, 1991
Does tube
feeding cause
Glycylglutamine: Metabolism and Effects on Organ Balances of Amino Acids in Postabsorptive and Starved Subjects H. LOCHS, W. HUBL, S. GASIC, American Journal
ET AL.
of Physiology 262 (Endocrinology and Metabolism 25): E155-E160, 1992
Abstract: 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. =
=
equilibration period, primed, conindocyanine green dye and p-aminohippurate were begun to assess hepatic, muscle (right lower extremity), and renal plasma flow. After a 45minute 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
During
a
30-minute
stant infusions of
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
Downloaded from pen.sagepub.com at SETON HALL UNIV on March 28, 2015
490 ± 4 to 31 ± 5 and 14 ± 2 to 19 ± 2 μmol/min, respectively) but had no similar effect on the starved subject.
that
Comment: The authors have had a long-standing interest in the potential nutritional applications of dipeptides.1-5 In one of their previous studies,’ they investigated metabolic clearance rates and organ fluxes of acetyl-, glycyl-, and alanylglutamine in conscious dogs fasted for 18 hours. Of these three sources of glutamine, the authors concluded that glycylglutamine appeared to be the preferable substrate if the objective was to target glutamine for the kidney. The present study extends the investigation of glycylglutamine to human subjects in the postabsorptive and mildly starved state. From the present study, the authors formulated several conclusions. Starvation caused increased net renal production of branched-chain and aromatic amino acids in addition to increased net renal production of glutamate. This suggests that even mild starvation increases renal proteolysis. The increased renal production of glutamate was accompanied by a doubling in net renal glutamine uptake suggesting that glutamine is the principal substrate for enhanced renal ammoniagenesis during starvation. Although starvation did not significantly increase net splanchnic alanine uptake in this study, there was a significant increase in the overall splanchnic uptake of gluconeogenic amino acids. The authors note that the most noteworthy effect of glycylglutamine was a modest, but significant, decrease in net alanine release from muscle in starved subjects (-27 ±3 to -23 ± 2 pmol/min) accompanied by a decrease in the arterial alanine level (185 ± 10 to 172 ± 7 ~M). The authors suggest that the mechanism is most likely not due to a decrease in proteolysis as net muscle release of other amino acids was not affected. However, mechanisms were not the focus of this investigation and this conclusion remains speculative. Nevertheless, the fact that the authors can detect changes in amino acid flux after only two hours of dipeptide infusion, suggests
garding the metabolism of glycylglutamine. As in the prior studies in dogs,’ the kidney appeared to be the predominant site of dipeptide clearance. The fact that splanchnic and muscle clearances of glycylglutamine were not significantly different between postabsorptive and starved subjects, whereas renal clearance of the dipeptide decreased with starvation, suggests that membrane hydrolysis was not impaired by starvation. The
more
specific experiments targeting proteolysis
would be warranted. The investigators also reached
some
conclusions
re-
authors concluded that the reduction in clearance of glycylglutamine by the kidney could be due to a reduction in the activity of the peptide transport system. Again, this remains speculative. Overall, this study demonstrates that glycylglutamine can be infused into human subjects and that small changes in amino acid flux within major organ beds can be detected. Further studies which investigate whether these changes in amino acid flux translate into either improved nutritional parameters or improved patient outcome remain to be performed. RICHARD E. GOLDSTEIN, MD Vanderbilt University Nashville, Tennessee REFERENCES
NN, Morse EL, Lochs H, et al: Possible sources of glutamine for parenteral nutrition: Impact on glutamine. Am J Physiol 257(Endocrinol Metab 20): E228-E234, 1989 Adibi SA: Intravenous use of glutamine in peptide form: Clinical applications of old and new observations. Metab Clin Exp 38:89-
1. Abumrad
2.
92, 1989 3. Adibi SA, Krzysik BA, Drash AL: Metabolism of intravenously administered dipeptides in rats: Effects on amino acid pools, glucose concentration and insulin and glucagon secretion. Clin Sci Mol Med 52:193-204, 1977 4. Lochs H, Morse EL, Adibi SA: Mechanism of hepatic assimilation of dipeptides. J Biol Chem 261:14976-14981, 1986 5. Lochs H, Morse EL, Adibi SA: Uptake and metabolism of dipeptides by human red blood cells. Biochem J 271:133-137, 1990
Downloaded from pen.sagepub.com at SETON HALL UNIV on March 28, 2015
comparable with that
DOUGLAS C. HEIMBURGER, MD Departments of Nutrition Sciences and Medicine University of Alabama at Birmingham Birmingham, Alabama REFERENCES 1.
2.
Kelly TWJ, Patrick MR, Hillman KM: Study of diarrhea in critically ill patients. Crit Care Med 11:7-9, 1983 Edes TE, Walk BE, Austin JL: Diarrhea in tube-fed patients: Feeding formula not necessarily the cause. Am J Med 88:91-93, 1990
3.
Heimburger DC, Sockwell DG, Geels WJ. diarrhea? Am J Clin Nutr 53:P-19, 1991
Does tube
feeding cause
Glycylglutamine: Metabolism and Effects on Organ Balances of Amino Acids in Postabsorptive and Starved Subjects H. LOCHS, W. HUBL, S. GASIC, American Journal
ET AL.
of Physiology 262 (Endocrinology and Metabolism 25): E155-E160, 1992
Abstract: 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. =
=
equilibration period, primed, conindocyanine green dye and p-aminohippurate were begun to assess hepatic, muscle (right lower extremity), and renal plasma flow. After a 45minute 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
During
a
30-minute
stant infusions of
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
Downloaded from pen.sagepub.com at SETON HALL UNIV on March 28, 2015
490 ± 4 to 31 ± 5 and 14 ± 2 to 19 ± 2 μmol/min, respectively) but had no similar effect on the starved subject.
that
Comment: The authors have had a long-standing interest in the potential nutritional applications of dipeptides.1-5 In one of their previous studies,’ they investigated metabolic clearance rates and organ fluxes of acetyl-, glycyl-, and alanylglutamine in conscious dogs fasted for 18 hours. Of these three sources of glutamine, the authors concluded that glycylglutamine appeared to be the preferable substrate if the objective was to target glutamine for the kidney. The present study extends the investigation of glycylglutamine to human subjects in the postabsorptive and mildly starved state. From the present study, the authors formulated several conclusions. Starvation caused increased net renal production of branched-chain and aromatic amino acids in addition to increased net renal production of glutamate. This suggests that even mild starvation increases renal proteolysis. The increased renal production of glutamate was accompanied by a doubling in net renal glutamine uptake suggesting that glutamine is the principal substrate for enhanced renal ammoniagenesis during starvation. Although starvation did not significantly increase net splanchnic alanine uptake in this study, there was a significant increase in the overall splanchnic uptake of gluconeogenic amino acids. The authors note that the most noteworthy effect of glycylglutamine was a modest, but significant, decrease in net alanine release from muscle in starved subjects (-27 ±3 to -23 ± 2 pmol/min) accompanied by a decrease in the arterial alanine level (185 ± 10 to 172 ± 7 ~M). The authors suggest that the mechanism is most likely not due to a decrease in proteolysis as net muscle release of other amino acids was not affected. However, mechanisms were not the focus of this investigation and this conclusion remains speculative. Nevertheless, the fact that the authors can detect changes in amino acid flux after only two hours of dipeptide infusion, suggests
garding the metabolism of glycylglutamine. As in the prior studies in dogs,’ the kidney appeared to be the predominant site of dipeptide clearance. The fact that splanchnic and muscle clearances of glycylglutamine were not significantly different between postabsorptive and starved subjects, whereas renal clearance of the dipeptide decreased with starvation, suggests that membrane hydrolysis was not impaired by starvation. The
more
specific experiments targeting proteolysis
would be warranted. The investigators also reached
some
conclusions
re-
authors concluded that the reduction in clearance of glycylglutamine by the kidney could be due to a reduction in the activity of the peptide transport system. Again, this remains speculative. Overall, this study demonstrates that glycylglutamine can be infused into human subjects and that small changes in amino acid flux within major organ beds can be detected. Further studies which investigate whether these changes in amino acid flux translate into either improved nutritional parameters or improved patient outcome remain to be performed. RICHARD E. GOLDSTEIN, MD Vanderbilt University Nashville, Tennessee REFERENCES
NN, Morse EL, Lochs H, et al: Possible sources of glutamine for parenteral nutrition: Impact on glutamine. Am J Physiol 257(Endocrinol Metab 20): E228-E234, 1989 Adibi SA: Intravenous use of glutamine in peptide form: Clinical applications of old and new observations. Metab Clin Exp 38:89-
1. Abumrad
2.
92, 1989 3. Adibi SA, Krzysik BA, Drash AL: Metabolism of intravenously administered dipeptides in rats: Effects on amino acid pools, glucose concentration and insulin and glucagon secretion. Clin Sci Mol Med 52:193-204, 1977 4. Lochs H, Morse EL, Adibi SA: Mechanism of hepatic assimilation of dipeptides. J Biol Chem 261:14976-14981, 1986 5. Lochs H, Morse EL, Adibi SA: Uptake and metabolism of dipeptides by human red blood cells. Biochem J 271:133-137, 1990
Downloaded from pen.sagepub.com at SETON HALL UNIV on March 28, 2015
