Exercise improves albumin fractional synthetic rate in chronic hemodialysis patients.

OBJECTIVE: To determine whether exercise augments the improvements in fractional synthetic rate (FSR) of albumin observed with nutrition alone. DESIGN: Randomized crossover study. Each patient randomly participated in two protein metabolism kinetic studies using primed-constant infusion of (13C) leucine 2 h before, during and 2 h after hemodialysis. Plasma enrichments of (13C) leucine and (13C) ketoisocaproate were examined to determine the FSR of albumin. SETTING: General Clinical Research Center at Vanderbilt University Medical Center. SUBJECTS: Five chronic hemodialysis (CHD) patients. INTERVENTIONS: Intra-dialytic parenteral nutrition (IDPN) with or without exercise. RESULTS: Exercise performance during hemodialysis significantly improves the FSR of albumin beyond what is observed with IDPN alone (26.2+/-3.1% per day versus 17.7+/-1.9% per day, P<0.05). CONCLUSION: Exercise improves albumin fractional synthetic rate beyond what is observed with IDPN alone in the acute setting in CHD patients.

Insulin resistance is associated with skeletal muscle protein breakdown in non-diabetic chronic hemodialysis patients.

Deranged protein metabolism is known to complicate uremia. Insulin resistance is evident in chronic hemodialysis (CHD) patients. We hypothesized that the degree of insulin resistance would predict protein catabolism in non-diabetic CHD patients. We examined the relationship between Homeostasis Model Assessment (HOMA) and fasting whole-body and skeletal muscle protein turnover in 18 non-diabetic CHD patients using primed-constant infusions of L-(1-(13)C) leucine and L-(ring-(2)H(5)) phenylalanine. Mean+/-s.d. fasting glucose and body mass index were 80.6+/-9.8 mg/dl and 25.4+/-4.4 kg/m(2), respectively. Median (interquartile range) HOMA was 1.6 (1.4, 3.9). Mean+/-s.e.m. skeletal muscle protein synthesis, breakdown, and net balance were 89.57+/-11.67, 97.02+/-13.3, and -7.44+/-7.14 microg/100 ml/min, respectively. Using linear regression, a positive correlation was observed between HOMA and skeletal muscle protein synthesis (R(2)=0.28; P=0.024), and breakdown (R(2)=0.49; P=0.001). An inverse association between net skeletal muscle protein balance and HOMA was also noted (R(2)=0.20; P=0.066). After adjustment for C-reactive protein, only the relationship between HOMA and skeletal muscle protein breakdown persisted (R(2)=0.49; P=0.006). There were no significant associations between components of whole-body protein turnover and HOMA. This study demonstrates that insulin resistance is evident in non-diabetic dialysis patients, is associated with skeletal muscle protein breakdown, and represents a novel target for intervention in uremic wasting.

Postexercise nutrient intake timing in humans is critical to recovery of leg glucose and protein homeostasis.

Although the importance of postexercise nutrient ingestion timing has been investigated for glycogen metabolism, little is known about similar effects for protein dynamics. Each subject (n = 10) was studied twice, with the same oral supplement (10 g protein, 8 g carbohydrate, 3 g fat) being administered either immediately (EARLY) or 3 h (LATE) after 60 min of moderate-intensity exercise. Leg blood flow and circulating concentrations of glucose, amino acids, and insulin were similar for EARLY and LATE. Leg glucose uptake and whole body glucose utilization (D-[6,6-2H(2)]glucose) were stimulated threefold and 44%, respectively, for EARLY vs. LATE. Although essential and nonessential amino acids were taken up by the leg in EARLY, they were released in LATE. Although proteolysis was unaffected, leg (L-[ring-2H(5)]phenylalanine) and whole body (L-[1-13C]leucine) protein synthesis were elevated threefold and 12%, respectively, for EARLY vs. LATE, resulting in a net gain of leg and whole body protein. Therefore, similar to carbohydrate homeostasis, EARLY postexercise ingestion of a nutrient supplement enhances accretion of whole body and leg protein, suggesting a common mechanism of exercise-induced insulin action.

Increased bone turnover is associated with protein and energy metabolism in adolescents with sickle cell anemia.

Contribution of bone turnover to the hypercatabolic state observed in sickle cell anemia is unknown. We examined the association between markers of bone turnover and basal rates of whole body protein turnover and energy expenditure in 28 adolescents with homozygous sickle cell anemia (HbSS) and in 26 matched controls with normal phenotype (HbAA). Whole body protein breakdown and synthesis were measured using a stable isotope of [15N]glycine, resting energy expenditure was measured by whole room indirect calorimetry, and the rate of pyridinoline cross-link (PYD) excretion in urine and fasting serum levels of the type I procollagen carboxy-terminal propeptide (PICP) were measured with commercial kits. Urinary PYD and serum PICP were significantly elevated in HbSS patients. The increase in procollagen synthesis, indicated by high levels of PICP, was significantly correlated with increased whole body protein synthesis. The increase in type I collagen degradation, indicated by high PYD excretion, was significantly correlated with increased protein breakdown. We conclude that increased rates of bone turnover contribute to the increased rates of protein turnover and energy expenditure observed in adolescents with homozygous sickle cell anemia.

Gastrointestinal tract, hepatic, hindlimb, and renal recovery of CO(2) in vivo.

Whole body oxidative rates of labeled substrates are often measured by collecting expired air and determining the amount of labeled CO(2) that is produced. However, the CO(2) produced may not be completely recovered under all circumstances, and there is a wide variation in values reported under different experimental conditions ( approximately 50-100%). The potential contribution of specific organs to this variation has not been defined. In vivo studies using healthy, postabsorptive, multicatheterized conscious canines were conducted to determine gastrointestinal tract, hepatic, hindlimb, and renal recoveries of NaH(14)CO(3) during a 180-min constant infusion [0.022+/-0.002 (SE) microCi x kg(-1) x min(-1)]. Before the constant infusion period, a bolus infusion of NaH(14)CO(3) (1.76+/-0.16 microCi/kg) was given, and the rate of decay in blood was measured over a 15-min period to determine pool size. The pool size for the distribution of (14)CO(2) was approximately 80% of the total body pool (16.0+/-1.7 liters). Whole body recovery was 97.2+/-6.7%. The recoveries across the liver, gut, leg, and kidney were 99.9+/-1.3, 98.0 +/-1.4, 96.7+/-2.6, and 99.9+/-2.1%, respectively. In conclusion, hepatic, gastrointestinal tract, hindlimb, and renal recoveries of CO(2) in vivo were near 100%, suggesting that CO(2) loss is not greater in gluconeogenic organs and that corrections for incomplete recovery of CO(2), when measuring oxidation of substrates across these organs under normal postabsorptive conditions, would be very minor.

Determination of stable isotopic enrichment and concentration of glycerol in plasma via gas chromatography-mass spectrometry for the estimation of lipolysis in vivo.

Measuring glycerol's rate of appearance into the plasma compartment provides an excellent estimation of whole-body lipolysis. The glycerol rate of appearance can be calculated by estimating the plasma dilution of continuously infused stable or radioactive isotopes of glycerol. Previously, determination of glycerol stable isotopic enrichment has required either chemical ionization gas chromatography-mass spectrometry (GC-MS) or electron impact ionization GC-MS in which a fragment containing only a portion of the glycerol molecule was measured. The present method uses tert.-butyldimethylsilyl (tBDMS) derivatization and electron impact ionization to measure a fragment including the entire glycerol molecule. The method determines concentration and enrichment of plasma glycerol in a simple, precise, and cost-efficient manner, providing a basis from which lipid homeostasis can be assessed.

Plasma leptin association with body composition and energy expenditure in sickle cell disease.

OBJECTIVE: To examine the association between fasting plasma leptin concentrations and the hypercatabolic state observed in sickle cell disease (SCD). METHODS: Plasma leptin concentration and resting energy expenditure (REE) were measured in 37 SCD patients (10 men, 12 boys 14 to 18 years-old, seven women, and eight girls 14 to 18 year-old) and in 37 age, gender and fat mass (FM) matched controls. Body composition was measured hydrostatically, REE by whole room-indirect calorimeter, and plasma leptin using an RIA kit. RESULTS: Plasma leptin concentration and leptin normalized for body fat (ng/dL*kg FM(-1)) were significantly lower in SCD patients than in non-SCD controls (4.00+/-3.23 vs. 9.94+/-14.69, p=0.021 and 0.406+/-0.260 vs. 0.643+/-0.561, p=0.024, respectively). A positive linear association between log plasma leptin and FM was observed in both males and females, adjusting for age and SCD status. The strength of this association was greater in females compared with males (slope=0.699 and 0.382 log ng/mL per 10 kg FM, respectively; p=0.013). SCD patients on average demonstrated a higher REE, adjusting for FFM (p<0.0001). Log plasma leptin and FM were not statistically significant predictors of REE after adjustment for FFM and SCD. CONCLUSIONS: Once corrected for body composition, mean plasma leptin concentration was significantly lower among female SCD patients than among non-SCD matched controls. Although REE was higher in SCD patients, there is no simple association between leptin and REE in SCD.

Net hepatic gluconeogenic amino acid uptake in response to peripheral versus portal amino acid infusion in conscious dogs.

These studies were conducted to determine the effect of route of gluconeogenic amino acid delivery on the hepatic uptake of the amino acids. After a sampling period with no experimental intervention (basal period), conscious dogs deprived of food for 42 h received somatostatin, intraportal infusions of insulin (3-fold basal) and glucagon (basal), and a peripheral infusion of glucose to increase the hepatic glucose load 1.5-fold basal for 240 min. A mixture of alanine, glutamate, glutamine, glycine, serine and threonine was infused intraportally at 7.6 micromol. kg(-1). min(-1) (PorAA group, n = 6) or peripherally at 8.1 micromol. kg(-1). min(-1) (PerAA, n = 6), to match the hepatic load of gluconeogenic amino acids in PorAA. During the infusion period, there were no differences in PerAA and PorAA, respectively, with regard to arterial plasma insulin (144 +/- 18 and 162 +/- 18 pmol/L), glucagon (51 +/- 8 and 47 +/- 11 ng/L), hepatic glucose load (199.8 +/- 22.2 and 210.9 +/- 16.6 micromol. kg(-1). min(-1)), net hepatic glucose uptake (2.8 +/- 2.2 and 2.2 +/- 1.7 micromol. kg(-1). min(-1)), hepatic load of amino acids (68 +/- 14 and 62 +/- 7 micromol. kg(-1). min(-1)), or net hepatic glycogen synthesis (11.1 +/- 2.2 and 8.9 +/- 2.2 micromol. kg(-1). min(-1)). The net hepatic uptake of glutamine (2.1 +/- 0.4 vs. 0.8 +/- 0.3 micromol. kg(-1). min(-1)) and the net hepatic fractional extractions of glutamine (0.11 +/- 0.02 vs. 0.05 +/- 0.02) and serine (0.41 +/- 0.03 vs. 0.34 +/- 0.02) were greater in PorAA than in PerAA (P < 0.05). We speculate that one or more of the amino acids in the mixture causes enhancement of the net hepatic uptake and fractional extraction of glutamine, and perhaps other gluconeogenic amino acids, during intraportal amino acid delivery.

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.

Comparison of air-displacement plethysmography with hydrostatic weighing and bioelectrical impedance analysis for the assessment of body composition in healthy adults.

BACKGROUND: Over the past decade, considerable attention has been paid to accurately measuring body composition in diverse populations. Recently, the use of air-displacement plethysmography (AP) was proposed as an accurate, comfortable, and accessible method of body-composition analysis. OBJECTIVE: The purpose of this study was to compare measurements of percentage body fat (%BF) by AP and 2 other established techniques, hydrostatic weighing (HW) and bioelectrical impedance analysis (BIA), in adults. DESIGN: The sample consisted of healthy men (n = 23) and women (n = 24). %BF was measured by AP, HW, and BIA. RESULTS: In the total group, %BF(AP) (25.0+/-8.9%) was not significantly different from %BF(HW) (25.1+/-7.7%) or %BF(BIA) (23.9+/-7.7%), and %BF(AP) was significantly correlated with %BF(HW) (r = 0.944, P < 0.001) and with %BF(BIA) (r = 0.859, P < 0.01). Compared with HW, AP underestimated %BF in men (by -1.24+/-3.12%) but overestimated %BF in women (by 1.02+/-2.48%), indicating a significant sex effect (P < 0.05). The differences in estimation between AP and BIA and between BIA and HW were not significantly different between the sexes. CONCLUSION: AP is an accurate method for assessing body composition in healthy adults. Future studies should assess further the cause of the individual variations with this new method.

The effect of nutritional and hormonal supplementation on protein synthesis immediately after liver transplantation.

We have previously shown that immediately after liver transplantation (LT) the porcine recipient exhibits elevated plasma glucagon, increased fractional synthetic rate (FSR) of fibrinogen, and decreased FSR of fixed or structural liver proteins. The purpose of this study was to evaluate the effect of nutritional and hormonal supplementation on these observations 24 h after LT. Two groups of nine pigs were studied 1 day after LT using radioisotopic and arteriovenous difference techniques. A control group underwent LT with saline infusion and a supplemented group underwent LT with infusion of glucose, amino acids (6 and 1.06 mg/kg. min, respectively), and intraportal insulin (0.6 mU/kg. min) and glucagon (1.3 ng/kg. min). Primed constant infusions of [3H]leucine were used to determine leucine flux, an estimate of whole body protein breakdown, and fractional synthetic rates (FSR). The following changes were noted with supplementation: elevated plasma insulin (6 +/- 1 versus 29 +/- 4 microU/ml, control versus supplemented, respectively, P < 0.05), decreased glucagon to normal levels (323 +/- 65 versus 102 +/- 12 pg/ml, P < 0.05), decreased fibrinogen FSR (108 +/- 15 versus 70 +/- 6%/day, P < 0.025), and increased fixed liver protein FSR (8 +/- 1 versus 13 +/- 2%/day, P < 0.05, respectively). Albumin FSR was unaltered by supplementation (8 +/- 2 versus 6 +/- 1%/day, respectively). Nutritional and hormonal supplementation immediately after LT restored the measured protein synthesis in the allograft to near normal levels 1 day after transplantation.

Differential effect of amino acid infusion route on net hepatic glucose uptake in the dog.

Concomitant portal infusion of gluconeogenic amino acids (GNGAA) and glucose significantly reduces net hepatic glucose uptake (NHGU), in comparison with NHGU during portal infusion of glucose alone. To determine whether this effect on NHGU is specific to the portal route of GNGAA delivery, somatostatin, intraportal insulin (3-fold basal) and glucagon (basal), and intraportal glucose (to increase the hepatic glucose load by approximately 50%) were infused for 240 min. GNGAA were infused peripherally into a group of dogs (PeAA), at a rate to match the hepatic GNGAA load in a group of dogs that were given the same GNGAA mixture intraportally (PoAA) at 7.6 micromol. kg-1. min-1 (9). The arterial blood glucose concentrations and hepatic glucose loads were the same in the two groups, but NHGU (-0. 9 +/- 0.2 PoAA and -2.1 +/- 0.5 mg. kg-1. min-1 in PeAA, P < 0.05) and net hepatic fractional extraction of glucose (2.6 +/- 0.7% in PoAA vs. 5.9 +/- 1.4% in PeAA, P < 0.05) differed. Neither the hepatic loads nor the net hepatic uptakes of GNGAA were significantly different in the two groups. Net hepatic glycogen synthesis was approximately 2.5-fold greater in PeAA than PoAA (P < 0.05). Intraportal, but not peripheral, amino acid infusion suppresses NHGU and net hepatic glycogen synthesis in response to intraportal glucose infusion.

Regulation of hepatic glutamine metabolism during exercise in the dog.

The goal of this study was to determine how liver glutamine (Gln) metabolism adapts to acute exercise in the 18-h-fasted dogs (n = 7) and in dogs that were glycogen depleted by a 42-h fast (n = 8). For this purpose, sampling (carotid artery, portal vein, and hepatic vein) and infusion (vena cava) catheters and Doppler flow probes (portal vein, hepatic artery) were implanted 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 [5-15N]Gln was initiated. Arterial Gln flux was determined by isotope dilution. Gut and liver Gln release into and uptake from the blood were calculated by combining stable isotopic and arteriovenous difference methods. The results of this study show that 1) in the 18-h-fasted dog, approximately 10% and approximately 35% of the basal Gln appearance in arterial blood is due to Gln release from the gut and liver, respectively, whereas approximately 30% and approximately 25% of the basal Gln disappearance is due to removal by these tissues; 2) extending the fast to 42 h does not affect basal arterial Gln flux or the contribution of the gut to arterial Gln fluxes but decreases hepatic Gln release, causing a greater retention of gluconeogenic carbon by the liver; 3) moderate-intensity exercise increases hepatic Gln removal from the blood regardless of fast duration but does not affect the hepatic release of Gln; and 4) Gln plays an important role in channeling nitrogen into the ureagenic pathway in the basal state, and this role is increased by approximately 80% in response to exercise. These studies illustrate the quantitative importance of the splanchnic bed contribution to arterial Gln flux during exercise and the ability of the liver to acutely adapt to changes in metabolic requirements induced by the combined effects of fasting and exercise.

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 insulin's 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.

Protein turnover and energy expenditure increase during exogenous nutrient availability in sickle cell disease.

In the present study, energy expenditure (EE) and rates of whole-body protein, glucose, and lipid metabolism were assessed in 8 African American sickle cell disease (SCD) patients and in 6 healthy African American control subjects during the infusion of amino acids, glucose, and lipid. Whole-body protein, glucose, and lipid kinetics were estimated by using L-[1-(13)C]leucine, D-[6,6-(2)H2]glucose, and [(2)H5]glycerol, respectively. After a 2-h tracer equilibration period and a 0.5-h basal period, nutrients were administered intravenously for 3 h with 16% of the energy as protein, 52% as carbohydrate, and 32% as fat. Breath and blood were collected during the last 30 min of nutrient infusion and EE was measured by indirect calorimetry. EE was 14% greater (P < or = 0.05) in SCD patients [145.0 +/- 3.5 kJ x kg fat-free mass (FFM)(-1) x d(-1)] than in control subjects (126.8 +/- 3.8 kJ x kg FFM(-1) x d(-1)). Whole-body protein breakdown (4.4 +/- 0.4 compared with 3.1 +/- 0.1 mg x kg FFM(-1) x min(-1), P < or = 0.05) and protein synthesis (4.6 +/- 0.4 compared with 3.2 +/- 0.1 g x kg FFM(-1) x min(-1), P < or = 0.05) were 42% and 44% greater, respectively, in the SCD patients than in control subjects, but whole-body amino acid oxidation (0.90 +/- 0.05 compared with 1.03 +/- 0.09 mg x kg FFM(-1) x min(-1)) was not significantly different between the 2 groups. Whole-body glucose and lipid kinetics did not differ significantly between the groups. EE increased in SCD patients during exogenous nutrient availability, and the additional energy required for the accelerated rates of whole-body protein breakdown and synthesis made a significant contribution to the increase in EE. These metabolic aberrations may increase the dietary energy and protein requirements of SCD patients.

Hepatic glucose disposition during concomitant portal glucose and amino acid infusions in the dog.

The effect of concomitant intraportal infusion of glucose and gluconeogenic amino acids (AA) on net hepatic glucose uptake (NHGU) and glycogen synthesis was examined in 42-h-fasted dogs. After a basal period, there was a 240-min experimental period during which somatostatin was infused continuously into a peripheral vein and insulin and glucagon (at 3-fold basal and basal rates, respectively) and glucose (18.3 mumol.kg-1.min-1) were infused intraportally. One group (PoAA, n = 7) received an AA mixture intraportally at 7.6 mumol.kg-1.min-1, whereas the other group (NoAA, n = 6) did not receive AA. Arterial blood glucose concentrations and hepatic glucose loads were the same in the two groups. NHGU averaged 4.8 +/- 2.0 (PoAA) and 9.4 +/- 2.0 (NoAA) mumol.kg-1.min-1 (P < 0.05), and tracer-determined hepatic glucose uptake was 4.6 +/- 1.6 (PoAA) and 10.0 +/- 1.7 (NoAA) mumol.kg-1.min-1 (P < 0.05). AA data for PoAA and NoAA, respectively, were as follows: arterial blood concentrations, 1,578 +/- 133 vs. 1,147 +/- 86 microM (P < 0.01); hepatic loads, 56 +/- 3 vs. 32 +/- 4 mumol.kg-1.min-1 (P < 0.01); and net hepatic uptakes, 14.1 +/- 1.4 vs. 5.6 +/- 0.4 mumol.kg-1.min-1 (P < 0.01). The rate of net hepatic glycogen synthesis was 7.5 +/- 1.9 (PoAA) vs. 10.7 +/- 2.3 (NoAA) mumol.kg-1.min-1 (P = 0.1). In a net sense, intraportal gluconeogenic amino acid delivery directed glucose carbon away from the liver. Despite this, net hepatic carbon uptake was equivalent in the presence and absence of amino acid infusion.

Net hepatic glucose output is normal on postoperative day 1 after liver transplantation.

The liver plays a central role in carbohydrate metabolism and glucose homeostasis; therefore, the rapid recovery of glucose homeostasis after liver transplantation (LT) is important. The purpose of this study was to evaluate hepatic and whole-body glucose production (WBGP) on postoperative day 1 after LT using a combination of arteriovenous differences and radioisotope techniques. Two groups of female commercially bred pigs with an average body weight of 31.9 +/- 1.4 kg were studied. A control group (n = 6) underwent laparotomy. A transplanted group (n = 6) was submitted to LT. All pigs were instrumented with catheters placed in the carotid artery and the hepatic, portal, and jugular vein, and flow probes were placed around the hepatic artery and portal vein. WBGP was measured by a primed constant infusion of 3-[3H]glucose 1 day postoperatively. Plasma glucose was 89 +/- 6 versus 98 +/- 7 mg/dL in the control and transplanted groups, respectively. WBGP was increased by 42 per cent in the transplanted group (2.54 +/- 0.17 vs 3.62 +/- 0.39 mg/kg.min), but the net hepatic glucose output was not different between the control and the transplanted groups (1.53 +/- 0.28 vs 1.68 +/- 0.31 mg/kg.min). These results demonstrate that net hepatic glucose output was not different between the control and transplanted pigs, suggesting that LT does not compromise the ability of the liver to produce glucose. However, the WBGP was increased by 42 per cent in the transplanted group, suggesting either a significant contribution from another organ or a significant intrahepatic utilization of glucose.

Hepatic uptake of amino acids immediately after liver transplantation is well preserved despite altered plasma profiles.

BACKGROUND: The liver is one of the principal organs responsible for the uptake and release of amino acids in the body. The ability of the transplanted liver to clear plasma amino acids is associated with a functioning allograft. However, clinical assessment is limited by the inability to access the portal vein postoperatively. Therefore, using a porcine liver transplant model, we examined (1) the plasma levels of amino acids presented to the new hepatic allograft and (2) the capacity of the new allograft to clear these amino acids from the circulation. MATERIALS AND METHODS: Two groups of commercially bred pigs were studied: a control group (n = 8) underwent laparotomy and a transplanted group (n = 6) underwent orthotopic liver transplantation (LT) using veno-venous bypass. All pigs had catheters placed in the carotid artery and portal and hepatic veins and ultrasonic transit time flow probes placed around the hepatic artery and portal vein. Plasma profiles of 23 amino acids were analyzed by high-pressure liquid chromatography. Hepatic balances of amino acids, using arteriovenous difference techniques coupled with hepatic blood flows, were also analyzed on postoperative day 1. RESULTS: Neither portal vein blood flow (703 +/- 74 ml/min vs 666 +/- 82 ml/min) nor hepatic artery blood flow (322 +/- 43 ml/min vs 209 +/- 59 ml/min) was significantly different between the control and the transplanted groups, respectively. The transplanted group had significantly increased plasma levels of alanine (135 +/- 13 mumol/l vs 382 +/- 72 mumol/l), hydroxyproline (30 +/- 5 mumol/l vs 60 +/- 9 mumol/l), methionine (25 +/- 2 mumol/l vs 55 +/- 10 mumol/l), ornithine (36 +/- 5 mumol/l vs 141 +/- 33 mumol/l), phenylalanine (84 +/- 5 mumol/l vs 120 +/- 12 mumol/l), threonine (75 +/- 9 mumol/l vs 159 +/- 27 mumol/l), and tryptophan (17 +/- 2 mumol/l vs 31 +/- 4 mumol/l). The transplanted group also had significantly decreased plasma levels of isoleucine (122 +/- 12 mumol/l vs 85 +/- 8 mumol/l) and taurine (71 +/- 7 mumol/l vs 35 +/- 7 mumol/l). These individual amino acid changes were not accompanied by impairment in the net hepatic amino acid balance or the hepatic fractional extraction of amino acids between the two groups. CONCLUSION: These results suggest that the circumstances associated with liver transplantation alter the fasting amino acid profile immediately postoperatively. However, liver transplantation does not impair the normal hepatic allograft uptake of most plasma amino acids. Thus, the changes observed in the circulating levels of amino acids may represent alterations in nonhepatic production and/or utilization. Furthermore, altered plasma amino acid profiles following liver transplantation are not necessarily indicative of impaired hepatic allograft amino acid metabolism.

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.

Mechanisms of hyperinsulinemia and hyperglucagonemia after liver transplantation.

These studies were undertaken to evaluate the mechanisms for changes in plasma insulin and glucagon levels observed post-liver transplantation. Two groups of pigs were studied: a control group (n = 8) underwent laparotomy and catheter placement in the carotid artery and portal and hepatic veins. Hepatic blood flow was measured by ultrasonic flow probes placed around the hepatic artery and portal vein. An experimental group (n = 8) underwent orthotopic liver transplantation and similar instrumentation. On Day 1 after surgery, an estimate of insulin and glucagon secretion and hepatic extraction was determined using arteriovenous difference techniques. Serum assays were performed for markers of hepatic and renal function. Plasma insulin levels of the transplanted pigs were higher in the carotid artery (4 +/- 1 microU/ml vs 7 +/- 1 microU/ml), but not in the hepatic vein (5 +/- 1 microU/ml vs 7 +/- 1 microU/ml) and in the portal vein (10 +/- 2 microU/ml vs 12 +/- 2 microU/ml). Arterial plasma C-peptide was significantly greater in the transplanted group (0.23 +/- 0.02 ng/ml vs 0.42 +/- 0.03 ng/ml); however, the molar ratio of C-peptide and insulin was not different between the two groups (3.6 +/- 0.9 vs 3.4 +/- 0.4). Plasma glucagon levels of the transplanted pigs were significantly elevated in the carotid artery (111 +/- 11 pg/ml vs 323 +/- 65 pg/ml), portal vein (221 +/- 27 pg/ml vs 495 +/- 69 pg/ml), and hepatic vein (142 +/- 15 pg/ml vs 395 +/- 58 pg/ml). The estimate of pancreatic secretion of insulin (115 +/- 28 microU/kg.min) vs 71 +/- 21 microU/kg.min) and glucagon (2.0 +/- 0.4 ng/kg.min vs 2.7 +/- 0.7 ng/kg.min) and the fractional hepatic extraction rate of insulin (35 +/- 8% vs 32 +/- 5%) were not different between the two groups. However, the hepatic fractional extraction rate of glucagon was significantly decreased in the transplanted group (25 +/- 5% vs 11 +/- 3%). Therefore, the hyperglucagonemia observed 24 hr following liver transplantation is partly due to reduced hepatic fractional extraction of glucagon while the hyperinsulinemia is mainly due to the nonhepatic clearance of insulin. We speculate that decreased renal function may contribute to the hyperinsulinemia, elevated C-peptide concentrations, and hyperglucagonemia.