Paul J. Flakoll

Intradialytic parenteral nutrition improves protein and energy homeostasis in chronic hemodialysis patients

Decreased dietary protein intake and hemodialysis-associated protein catabolism are among several factors that predispose chronic hemodialysis (CHD) patients to protein calorie malnutrition. Since attempts to increase protein intake by dietary counseling are usually ineffective, intradialytic parenteral nutrition (IDPN) has been proposed as a potential therapeutic approach in malnourished CHD patients. In this study, we examined protein and energy homeostasis during hemodialysis in seven CHD patients at two separate hemodialysis sessions, with and without IDPN administration. Patients were studied 2 hours before, during, and 2 hours following a hemodialysis session, using a primed constant infusion of L-(1-(13)C) leucine and L-(ring-(2)H(5)) phenylalanine. Our results showed that IPDN promoted a large increase in whole-body protein synthesis and a significant decrease in whole-body proteolysis, along with a significant increase in forearm muscle protein synthesis. The net result was a change from an essentially catabolic state to a highly positive protein balance, both in whole-body and forearm muscle compartments. We conclude that the provision of calories and amino acids during hemodialysis with IDPN acutely reverses the net negative whole-body and forearm muscle protein balances, demonstrating a need for long-term clinical trials evaluating IDPN in malnourished CHD patients.

Postexercise protein intake enhances whole-body and leg protein accretion in humans.

PURPOSE Exercise increases the use of amino acids for glucose production and stimulates the oxidation of amino acids and other substrates to provide ATP for muscular contraction, and thus the availability of amino acids and energy for postexercise muscle protein synthesis may be limiting. The purpose of this study was to determine the potential of postexercise nutrient intake to enhance the recovery of whole-body and skeletal muscle protein homeostasis in humans. METHODS Primed-continuous infusions of L-[1-13C]leucine and L-[ring-2H5]phenylalanine were initiated in the antecubital vein and blood was sampled from a femoral vein and a heated (arterialized) hand vein. Each study consisted of a 30-min basal, a 60-min exercise (bicycle at 60% VO2max), and a 180-min recovery period. Five men and five women were studied three times with an oral supplement administered immediately following exercise in random order: NO = 0, 0, 0; SUPP = 0, 8, 3; or SUPP+PRO = 10, 8, 3 g of protein, carbohydrate, and lipid, respectively. RESULTS Compared to NO, SUPP did not alter leg or whole-body protein homeostasis during the recovery period. In contrast, SUPP+PRO increased plasma essential amino acids 33%, leg fractional extraction of phenylalanine 4-fold, leg uptake of glucose 3.5-fold, and leg and whole-body protein synthesis 6-fold and 15%, respectively. Whereas postexercise intake of either NO or SUPP resulted in a net leg release of essential amino acids and net loss of whole-body and leg protein, SUPP+PRO resulted in a net leg uptake of essential amino acids and net whole-body and leg protein gain. CONCLUSIONS These findings suggest that the availability of amino acids is more important than the availability of energy for postexercise repair and synthesis of muscle proteins.

Intradialytic Oral Nutrition Improves Protein Homeostasis in Chronic Hemodialysis Patients with Deranged Nutritional Status

Decreased dietary protein intake and hemodialysis (HD)-associated protein catabolism predispose chronic HD (CHD) patients to deranged nutritional status, which is associated with poor clinical outcome in this population. Intradialytic parenteral nutrition (IDPN) reverses the net negative whole-body and skeletal muscle protein balance during HD. IDPN is costly and restricted by Medicare and other payers. Oral supplementation (PO) is a more promising, physiologic, and affordable intervention in CHD patients. Protein turnover studies were performed by primed-constant infusion of L-(1-(13)C) leucine and L-(ring-(2)H(5)) phenylalanine in eight CHD patients with deranged nutritional status before, during, and after HD on three separate occasions: (1) with IDPN infusion, (2) with PO administration, and (3) with no intervention (control). Results showed highly positive whole-body net balance during HD for both IDPN and PO (4.43 +/- 0.7 and 5.71 +/- 1.2 mg/kg fat-free mass per min, respectively), compared with a neutral balance with control (0.25 +/- 0.5 mg/kg fat-free mass per min; P = 0.002 and <0.001 for IDPN versus control and PO versus control, respectively). Skeletal muscle protein homeostasis during HD also improved with both IDPN and PO (50 +/- 19 and 42 +/- 17 microg/100 ml per min) versus control (-27 +/- 13 microg/100 ml per min; P = 0.005 and 0.009 for IDPN versus control and PO versus control, respectively). PO resulted in persistent anabolic benefits in the post-HD phase for muscle protein metabolism, when anabolic benefits of IDPN dissipated (-53 +/- 25 microg/100 ml per min for control, 47 +/- 41 microg/100 ml per min for PO [P = 0.039 versus control], and -53 +/- 24 microg/100 ml per min for IDPN [P = 1.000 versus control and 0.039 versus PO]). Long-term studies using intradialytic oral supplementation are needed for CHD patients with deranged nutritional status.

A Comparison of Air Displacement Plethysmography with Three Other Techniques to Determine Body Fat in Healthy Adults

BACKGROUND This study compared air displacement plethysmography (ADP), which relies on measurements of body density to estimate body fat, with three other techniques that measure body composition: (1) hydrostatic weighing (HW), which also measures body density; (2) bioelectrical impedance (BIA), which determines electrical resistance and total body water to estimate fat-free mass; and (3) dual-energy x-ray absorptiometry (DXA), which measures bone, fat, and fat-free soft tissue masses. METHODS ADP, HW, BIA, and DXA were performed on 20 healthy volunteers (10 males and 10 females). The subjects were within 20% of ideal body weight, 31.1 +/- 1.8 years of age, and 75.4 +/- 2.7 kg with body mass index values of 25.2 +/- 0.9 (kg/m2) and percent body fat by ADP ranging from 6.0% to 41.0%. RESULTS Percent body fat measurements by the four methods were highly correlated (r > .90, p < .0001). Mean body fat as determined by ADP, HW, BIA, and DXA were 23.4% +/- 2.3%, 23.9% +/-1.8%, 23.1% +/- 1.9%, and 26.4% +/- 2.4%, respectively (* p < .05 vs ADP). There was a significantly positive slope (+0.23) for the individual differences vs the average of ADP and HW percent body fat, demonstrating a slightly negative difference at lower body fat levels and a slightly positive difference at greater body fat levels. Although the average percent body fat determined by ADP was similar to that by HW for the entire population, there was a significant gender difference with the average body fat measured by ADP being 16% less in males and 7% greater in females than that determined by HW. CONCLUSIONS Body fat measurements using ADP were highly correlated with those using HW, BIA, and DXA across a relatively wide range of body fat levels in healthy adults. These results support the utility of ADP as a relatively new technique in the estimation of percent body fat in healthy adults. However, the error associated with gender and the level of body fat is not negligible and requires further investigation.

Year-long changes in protein metabolism in elderly men and women supplemented with a nutrition cocktail of β-hydroxy-β-methylbutyrate (HMB), L-arginine, and L-lysine.

BACKGROUND A major contributing factor to the loss of mobility in elderly people is the gradual and continuous loss of lean body mass. OBJECTIVES To determine whether supplementation of an amino acid cocktail daily for 1 year could improve the age-associated changes in protein turnover and lean body mass in elderly people. DESIGN Elderly (76+/-1.6 years) women (n=39) and men (n=38) were recruited for a double-blinded controlled study. Study participants were randomly assigned to either an isonitrogenous control-supplement (n=37) or a treatment-supplement (HMB/Arg/Lys) consisting of beta-hydroxy-beta-methylbutyrate, L-arginine, and L-lysine (n=40) for the 1-year study. Lean tissue mass was measured using both bioelectrical-impedance analysis (BIA) and dual energy x-ray absorptiometry (DXA). Rates of whole-body protein turnover were estimated using primed/intermittent oral doses of 15N-glycine. RESULTS In subjects taking the HMB/Arg/Lys supplement, lean tissue increased over the year of study while in the control group, lean tissue did not change. Compared with control, HMB/Arg/Lys increased body cell mass (BIA) by 1.6% (P=.002) and lean mass (DXA) by 1.2% (P=.05). The rates of protein turnover were significantly increased 8% and 12% in the HMB/Arg/Lys-supplemented group while rates of protein turnover decreased 11% and 9% in the control-supplemented subjects (P<.01), at 3 and 12 months, respectively. CONCLUSIONS Consumption of a simple amino acid-related cocktail increased protein turnover and lean tissue in elderly individuals in a year-long study.

Nutritional Supplementation Acutely Increases Albumin Fractional Synthetic Rate in Chronic Hemodialysis Patients

Uremic malnutrition is associated with increased risk of hospitalization and death in chronic hemodialysis (CHD) patients. Most nutritional intervention studies in CHD patients traditionally have used concentrations of serum albumin as the primary outcome measure and showed slight or no significant improvements. A recent study showed that intradialytic parenteral nutrition (IDPN) improves whole-body protein synthesis in CHD patients. On the basis of this observation, it was hypothesized that the anabolic effects of IDPN are associated with increases in the fractional synthetic rate of albumin, a direct estimate of acute changes in hepatic albumin synthesis. Seven CHD patients were studied during two hemodialysis (HD) sessions, with and without IDPN, using primed-constant infusion of (13C) leucine 2 h before, during, and 2 h after HD. Plasma enrichments of (13C) leucine and (13C) ketoisocaproate were examined to determine the fractional synthetic rate of albumin. The results indicate that administration of IDPN significantly improves the fractional synthetic rate of albumin during HD (16.2 +/- 1.5%/d versus 12.8 +/- 1.7%/d; P < 0.05) in CHD patients in parallel with significant improvements in whole-body protein synthesis (5.05 +/- 1.3 mg/kg fat-free mass/min versus 3.22 +/- 0.3 mg/kg fat-free mass/min; P < 0.05). IDPN is protein anabolic in the acute setting in CHD patients, as evidenced by significant concomitant increases in the fractional synthetic rate of albumin and whole-body protein synthesis.

Parenteral glutamine infusion alters insulin-mediated glucose metabolism.

BACKGROUND Glutamine is a conditionally essential amino acid that is critical for many basic cellular processes. Its supplementation has been found to be beneficial during several critical illnesses. This study examines the effects of increased glutamine availability on insulin-mediated glucose homeostasis in vivo in multicatheterized conscious canines (n = 5). METHODS Two weeks before the study, catheters were placed in the femoral artery and the portal, hepatic, femoral, and renal veins for blood sampling and in the splenic vein for intraportal infusion of insulin and glucagon. Doppler probes were placed to measure blood flow. The metabolic study consisted of equilibration, basal, and experimental periods during which [3-3H]glucose was infused to measure glucose kinetics. During the 5-hour experimental period, a hyperinsulinemic-euglycemic clamp was performed by infusing somatostatin, basal glucagon, fivefold basal insulin, and glucose to maintain euglycemia. The experimental period was divided evenly into two subperiods performed in random order: (1) i.v. glutamine infusion (0.72 mmol kg(-1) h(-1)) and (2) i.v. saline infusion. RESULTS With glutamine, the glucose required to maintain euglycemia was increased 46% over saline (6.8 +/- 1.0 to 9.9 +/- 1.7 mg kg(-1) min(-1). In addition, whole-body glucose production and utilization were increased by 1.4 and 4.6 mg kg(-1) min(-1), respectively. Finally, the increase in whole-body glucose utilization was manifested by increased hepatic and hindlimb glucose utilization. CONCLUSIONS Increased glutamine availability blunted insulins action on glucose production and enhanced insulin-mediated glucose utilization with the changes in utilization being threefold greater than the changes in production. Thus parenteral glutamine has potential benefit as a nutrient adjuvant during clinical situations associated with insulin resistance.

Short-term regulation of insulin-mediated glucose utilization in four-day fasted human volunteers: role of amino acid availability

SummaryGlucose homeostasis in men fasted for 84 h was assessed using isotopes, indirect calorimetry and forearm balance techniques during a basal period and three sequential hyperinsulinaemic euglycaemic clamps each lasting for 150 min. Two protocols (n=12 in each) were used: subjects were either allowed to develop hypoaminoacidaemia or received a commercial solution of L-amino acids while maintaining near-basal plasma leucine levels. Insulin infusions resulted in 3-, 35- and 650-fold increases in plasma insulin levels in both protocols. The infusion of amino acids produced a rightward shift in the dose-response curve of insulins effect on suppressing hepatic glucose production, indicating decreased sensitivity in addition to blunting of the maximal responsiveness. Total body glucose rate of disappearance was progressively increased with escalating insulin doses, but was 22% lower at the intermediate and highest insulin doses in the group that was infused with amino acids (3.44±0.53 vs 4.82±0.71 and 7.72±1.01 vs 10.36±1.08 mg·kg−1·min−1, respectively; p<0.05). Forearm balance data confirmed the isotopic data, since amino acid infusions blunted the insulin-mediated increase in net forearm glucose utilization (by 50–83%). Furthermore, the infusion of amino acids resulted in marked reductions in the rate of carbohydrate oxidation and storage as assessed by indirect calorimetry. The data indicate that the amino acid-mediated suppression of glucose utilization and carbohydrate oxidation is exerted on the responsive component of insulin action.

Alterations in basal nutrient metabolism increase resting energy expenditure in sickle cell disease

Basal rates of whole body protein, glucose, and lipid metabolism and resting energy expenditure (REE) were measured in eight African-American sickle cell disease (SCD) patients and in six African-American controls. Catheters were placed 1) in an antecubital vein for stable isotope infusion and 2) in a heated hand vein for arterialized venous blood. Breath and blood were collected during the last 30 min of the 2.5-h study, and REE was measured by indirect calorimetry. REE [128 ± 5 vs. 111 ± 1 kJ ⋅ kg fat-free mass (FFM)-1 ⋅ day-1; P < 0.05 vs. controls] was 15% greater in the SCD patients. Whole body protein breakdown (5.0 ± 0.3 vs. 3.8 ± 0.2 mg ⋅ kg FFM-1 ⋅ min-1; P < 0.05 vs. controls) and protein synthesis (4.4 ± 0.3 vs. 3.2 ± 0.2 mg ⋅ kg FFM-1 ⋅ min-1; P< 0.05 vs. controls) were 32 and 38% greater, respectively, in the SCD patients, but whole body amino acid oxidation was similar (0.58 ± 0.03 vs. 0.66 ± 0.03 mg ⋅ kg FFM-1 ⋅ min-1). Measures of whole body glucose and lipid metabolism were not significantly different between the groups. The additional energy required for the greater rates of whole body protein breakdown and synthesis caused by SCD contributes significantly to the observed increase in REE, suggesting that dietary energy and protein requirements are enhanced in SCD patients.Basal rates of whole body protein, glucose, and lipid metabolism and resting energy expenditure (REE) were measured in eight African-American sickle cell disease (SCD) patients and in six African-American controls. Catheters were placed 1) in an antecubital vein for stable isotope infusion and 2) in a heated hand vein for arterialized venous blood. Breath and blood were collected during the last 30 min of the 2.5-h study, and REE was measured by indirect calorimetry. REE [128 +/- 5 vs. 111 +/- 1 kJ.kg fat-free mass (FFM)-1.day-1; P < 0.05 vs. controls] was 15% greater in the SCD patients. Whole body protein breakdown (5.0 +/- 0.3 vs. 3.8 +/- 0.2 mg.kg FFM-1.min-1; P < 0.05 vs. controls) and protein synthesis (4.4 +/- 0.3 vs. 3.2 +/- 0.2 mg.kg FFM-1.min-1; P < 0.05 vs. controls) were 32 and 38% greater, respectively, in the SCD patients, but whole body amino acid oxidation was similar (0.58 +/- 0.03 vs. 0.66 +/- 0.03 mg.kg FFM-1.min-1). Measures of whole body glucose and lipid metabolism were not significantly different between the groups. The additional energy required for the greater rates of whole body protein breakdown and synthesis caused by SCD contributes significantly to the observed increase in REE, suggesting that dietary energy and protein requirements are enhanced in SCD patients.

Effect of physical activity and fasting on gut and liver proteolysis in the dog

The aim of this study was to determine how gut and liver protein kinetics adapt to acute exercise in the 18-h-fasted dog ( n = 7) and in dogs glycogen depleted by a 42-h fast ( n = 8). For this purpose, sampling (artery and portal and hepatic veins) and infusion (vena cava) catheters and Doppler flow probes (portal vein and hepatic artery) were implanted with animals under general anesthesia. At least 16 days later, an experiment, consisting of a 120-min equilibration period, a 30-min basal sampling period, and a 150-min exercise period, was performed. At the start of the equilibration period, a constant rate infusion of [1-13C]leucine was initiated. Gut and liver leucine appearance and disappearance rates were calculated in these studies by combining a novel stable isotopic method and arteriovenous difference methods. In the determination of tissue leucine kinetics the tissue inflow of both α-[13C]ketoisocaproic acid and [13C]leucine was taken into account. The results of this study show that 1) the splanchnic bed (liver plus gut) contributes ∼40% to the whole body proteolytic rate in the basal state and during exercise in dogs fasted for either 18 or 42 h, 2) the contributions of the gut and liver to splanchnic bed proteolysis is about equal in the basal state in both 18- and 42-h-fasted dogs, and 3) exercise in the 18-h-fasted dog leads to a greater emphasis on gut proteolysis and a lesser emphasis on hepatic proteolysis. These studies highlight the important contribution of gut and hepatic proteolysis to whole body proteolysis and the ability of the gut to acutely adapt to changes in physical activity.The aim of this study was to determine how gut and liver protein kinetics adapt to acute exercise in the 18-h-fasted dog (n = 7) and in dogs glycogen depleted by a 42-h fast (n = 8). For this purpose, sampling (artery and portal and hepatic veins) and infusion (vena cava) catheters and Doppler flow probes (portal vein and hepatic artery) were implanted with animals under general anesthesia. At least 16 days later, an experiment, consisting of a 120-min equilibration period, a 30-min basal sampling period, and a 150-min exercise period, was performed. At the start of the equilibration period, a constant rate infusion of [1-13C]leucine was initiated. Gut and liver leucine appearance and disappearance rates were calculated in these studies by combining a novel stable isotopic method and arteriovenous difference methods. In the determination of tissue leucine kinetics the tissue inflow of both alpha-[13C]ketoisocaproic acid and [13C]leucine was taken into account. The results of this study show that 1) the splanchnic bed (liver plus gut) contributes approximately 40% to the whole body proteolytic rate in the basal state and during exercise in dogs fasted for either 18 or 42 h, 2) the contributions of the gut and liver to splanchnic bed proteolysis is about equal in the basal state in both 18- and 42-h-fasted dogs, and 3) exercise in the 18-h-fasted dog leads to a greater emphasis on gut proteolysis and a lesser emphasis on hepatic proteolysis. These studies highlight the important contribution of gut and hepatic proteolysis to whole body proteolysis and the ability of the gut to acutely adapt to changes in physical activity.