Biomedical subjects

R R Wolfe

Publications and source records attributed to R R Wolfe.

At least 109 records · Page 6Linked to original sources

PubMed1996

Atrial natriuretic peptide and nitric oxide in children with pulmonary hypertension after surgical repair of congenital heart disease.

ANP causes pulmonary vasodilation in some children with pulmonary hypertension secondary to congenital heart disease. In a small group of patients, ANP lowered mean pulmonary artery pressure and pulmonary vascular resistance index > 20% without changing systemic vascular resistance index. Inhaled NO is an effective pulmonary vasodilator and is a more selective pulmonary vasodilator than ANP. The utility of ANP may be limited by its nonselective effects as more selective vasodilator agents are available.

Adolescent↗

PubMed1996

Effect of theophylline on substrate metabolism during exercise.

We tested the hypothesis that adenosine is involved in regulating substrate metabolism during exercise. Seven trained cyclists were studied during 30 minutes of exercise at approximately 75% maximal oxygen uptake (VO2max). Lipid metabolism was evaluated by infusing [2H5]glycerol and [1-13C]palmitate, and glucose kinetics were evaluated by infusing [6,6-2H]glucose. Fat and carbohydrate oxidation were also measured by indirect calorimetry. The same subjects performed two identical exercise tests, but in one trial theophylline, a potent adenosine receptor antagonist, was infused for 1 hour before and throughout exercise. Theophylline did not increase whole-body lipolysis (glycerol rate of appearance [Ra]) or free fatty acid (FFA) release during exercise, but fat oxidation was lower than control values (9.5 +/- 3.0 v 18.0 +/- 4.2 micromol x min(-1) x kg(-1), P < .01). Glucose Ra was not affected by theophylline infusion, but glucose uptake was lower (31.6 +/- 4.1 v 40.4 +/- 5.0 micromol x min(-1) x kg(-1), P < .05) and glucose concentration was higher (6.4 +/- 0.6 v 5.8 +/- 0.4 mmol/L, P < .05) than in the control trial. Total carbohydrate oxidation (302.3 +/- 26.2 v 265.5 +/- 11.7 micromol x min(-1) x kg(-1), P < .06), estimated muscle glycogenolysis (270.7 +/- 23.1 v 225.1 +/- 9.7 micromol x min(-1) x kg(-1), P < .05), and plasma lactate concentration (7.9 +/- 1.6 v 5.9 +/- 1.1 mmol/L, P < .001) were also higher during the theophylline trial. These data suggest that adenosine may play a role in stimulating glucose uptake and restraining glycogenolysis but not in limiting lipolysis during exercise.

Adult↗

PubMed1996

Effect of endurance training on glycerol kinetics during strenuous exercise in humans.

Glycerol kinetics were evaluated during high-intensity exercise in five untrained and five endurance-trained subjects. Glycerol rate of appearance (Ra) in plasma was determined by infusing [2H5]glycerol during rest and 60 minutes of cycle ergometer exercise performed at 70% V02 peak. Mean plasma glycerol concentration was greater in trained than untrained subjects throughout exercise (P<.05). The average glycerol Ra during exercise and the integrated lipolytic response to exercise, expressed as total glycerol Ra above baseline, were both greater in trained (7.85 +/- 0.72 micromol x kg(-1) x min(-1) and 289 +/- 50 micromol x kg(-1) x h(-1), respectively) than in untrained (5.68 +/- 0.90 micromol x kg(-1) x min(-1), and 198 +/- 31 micromol x kg(-1) x h(-1), respectively) subjects (P<.05). We conclude that whole-body lipolytic rates are greater in endurance-trained athletes than in sedentary controls during high-intensity exercise performed at the same relative intensity.

Adult↗

PubMed1996

An animal model for measurement of protein metabolism in the skin.

BACKGROUND: A suitable in vivo approach with which to quantify skin protein metabolism has not been found, and consequently no information exists relating protein synthesis to protein breakdown in the fasted state. METHODS: Stable isotope-labeled phenylalanine was infused into five fasted rabbits, and amino acid and protein kinetics were calculated from a three-compartment model with the rabbit ear used as an arteriovenous balance mode. Results were compared with the more traditional but limited direct incorporation technique to measure synthesis. RESULTS: The model-derived skin protein synthesis rate was 0.34%/hr +/- 0.04%/hr, which was almost identical to the value of 0.30%/hr +/- 0.01%/hr determined by the direct incorporation method. The model-derived skin protein breakdown rate was only slightly higher than the synthesis rate, meaning protein balance was generally maintained in the fasted state because of the efficient reuse of amino acids from protein breakdown. CONCLUSIONS: The newly described rabbit ear model is a reliable approach to the determination of the amino acid and protein kinetics in the skin in vivo. Efficient reuse of amino acids released from proteolysis explains the maintenance of skin integrity during brief fasting.

Animals↗

PubMed1996

Regulation of the acid-labile subunit of the insulin-like growth factor ternary complex in patients with insulin-dependent diabetes mellitus and severe burns.

OBJECTIVE: Little information is available regarding the regulation of serum acid-labile subunit (ALS) in human disease. We have studied alterations in serum ALS of the insulin-like growth factor (IGF) ternary complex in children with untreated insulin-dependent diabetes mellitus (IDDM) and subjects with severe burns before and after insulin therapy. In addition, we have investigated the effect of insulin plus GH on serum ALS in burn patients. DESIGN: Serum samples were obtained from children with newly diagnosed and untreated IDDM before the initiation of insulin therapy and 1 month thereafter. Serum samples were also obtained from adult patients with severe burns who were on a continuous infusion of a carbohydrate-rich enteral diet via nasogastric and duodenal catheters under basal conditions, after a 1-week period of continuous insulin infusion, and after an additional week of insulin plus recombinant GH. PATIENTS: Twenty children and adolescents with untreated IDDM, aged 1.2-16 years, and 6 young adult patients with severe burns aged 17-28 years were studied longitudinally. Control sera were obtained from age, sex and pubertal status matched subjects (for children with IDDM) and from fed healthy adults. MEASUREMENTS: Serum insulin, GH, cortisol and IGF-I were measured by radioimmunoassay, and serum ALS levels were assessed by Western immunoblot before and after treatment periods. RESULTS: Serum ALS levels were lower in untreated children with IDDM (69 +/- 6% of control children). Insulin therapy significantly increased serum ALS (79 +/- 5%, P < 0.05) in these children. Patients with severe burns also had lower serum ALS levels (79 +/- 10% of control adults). After one week of insulin therapy serum ALS levels increased to 90 +/- 15% of control values (P < 0.05). Addition of GH to insulin therapy for another week did not significantly further increase serum ALS levels (95 +/- 27%). Serum IGF-I concentrations increased nearly 2.5-fold in diabetic subjects and fourfold in burn subjects at the end of the study periods. There were no proteolytic fragments of ALS in the sera studied. The deglycosylation pattern of ALS did not differ between diabetic and control sera. CONCLUSION: Serum ALS levels were diminished in children with untreated IDDM and were partially restored after the initiation of insulin therapy. Serum ALS levels were also diminished in patients with severe burn injury and restored by insulin treatment. Addition of GH to insulin therapy did not significantly increase serum ALS levels over levels obtained during insulin therapy alone. These decreases in serum ALS were smaller than the decrease in serum IGF-I concentrations in both conditions, suggesting that IGF-I is the limiting factor for the ternary complex formation in the catabolic states. Insulin may regulate circulating ALS levels in catabolic states and helps to restore the IGF system.

Acute Disease↗

PubMed1996

Herman Award Lecture, 1996: relation of metabolic studies to clinical nutrition--the example of burn injury.

The optimal nutritional support of critically ill patients should be based on the metabolic response. Therefore, we performed a series of experiments in patients using stable isotopic tracers designed to elucidate the responses of glucose, fatty acids, and protein metabolism in severely burned patients. Glucose production was elevated above normal as a result of an increase in glucagon concentration. The peripheral hypoglycemic action of insulin was diminished, as was its effectiveness in suppressing endogenous glucose production, but the intracellular capacity to oxidize glucose was not impaired. Lipolysis was stimulated by beta 2-adrenergic stimulation to a much greater extent than was fatty acid oxidation, with the result being an increase in the recycling of fatty acids secreted in very-low-density lipoproteins. Muscle protein catabolism was accelerated in severely burned patients, leading to a progressive loss of lean body mass that was not prevented by nutritional support alone. The ineffectiveness of nutritional support for muscle was due to alterations in amino acid transmembrane transport kinetics that favored efflux. Treatment with exogenous insulin stimulated inward amino acid transport and muscle protein synthesis. Extrapolation from our current knowledge of metabolism to clinical treatment indicates that nonprotein energy should be provided largely in the form of carbohydrate. If hyperglycemia ensues, exogenous insulin will further increase the anabolic response in muscle. Protein requirements can be met with 1.5 g protein.kg-1.d-1. Treatment with anabolic hormones may ultimately be the most effective way in which to optimize the response to nutritional support.

Awards and Prizes↗

PubMed1996

Beta-blockade lowers peripheral lipolysis in burn patients receiving growth hormone. Rate of hepatic very low density lipoprotein triglyceride secretion remains unchanged.

OBJECTIVE: The purpose of this study was to determine the effect of propranolol on peripheral lipolysis in massively burned children during treatment with recombinant human growth hormone (rhGH), and to ascertain whether decreased free fatty acid availability for re-esterification would alter the hepatic rate of secretion of triglycerides (TGs) bound to very low density lipoproteins (VLDLs). BACKGROUND: Fatty liver occurs in severely burned patients, often resulting in a twofold increase in liver size. This could be the result of an imbalance between increased provision of free fatty acids from peripheral lipolysis, coupled with no increase in fat oxidation, and insufficient rate of secretion of TGs from the liver. METHODS: In a cross-over study, six burned children were treated with either rhGH or rhGH plus propranolol. On the sixth day of treatment, isotopic tracer infusions were conducted to determine the rate of release of free fatty acid (Ra FFA) from peripheral tissue and the rate of secretion of VLDL-bound TGs by the liver. RESULTS: Exogenous rhGH increased Ra FFA in children with large third-degree burns. Propranolol decreased Ra FFA, but the rate of secretion of fatty acids in the form of VLDL-TG from the liver was maintained. Plasma FFA, as opposed to fatty acids newly synthesized in the liver, were the primary precursors for hepatic triglyceride synthesis. CONCLUSIONS: The administration of propranolol to burned children receiving rhGH is safe, has salutary cardiovascular effects, decreases the release of FFA from adipose tissue and increases the efficiency of the liver in secreting fatty acids as VLDL TGs.

Adolescent↗

PubMed1996

Pyruvate dehydrogenase inactivity is not responsible for sepsis-induced insulin resistance.

OBJECTIVE: To determine whether activation of pyruvate dehydrogenase with dichloroacetate can reverse sepsis-induced insulin resistance in humans or rats. DESIGN: Prospective, controlled study. SETTING: Intensive care unit (ICU) and laboratory at a university medical center. SUBJECTS: Nine patients were admitted to the ICU with Gram-negative sepsis, confirmed by cultures. In addition, chronically instrumented, Sprague-Dawley rats, either controls or with live Escherichia coli-induced sepsis. INTERVENTIONS: Hyperinsulinemic euglycemic clamp, with or without coadministration of dichloroacetate. MEASUREMENTS AND MAIN RESULTS: In humans, a primed, constant infusion of [6,6-2H2]glucose was used to determine endogenous glucose production and whole-body glucose disposal. Septic humans exhibited impaired maximal insulin-stimulated glucose utilization (39.5 +/- 2.7 mumol/kg/min), despite complete suppression of endogenous glucose production. In rats, a primed, constant infusion of [3-3H]glucose was used to determine endogenous glucose production and whole-body glucose disposal. Tissue glucose uptake in vivo was determined by [14C]-2-deoxyglucose uptake. Maximal, whole-body, insulin-stimulated glucose utilization was 205 +/- 11 and 146 +/- 9 mumol/kg/min in control and septic rats, respectively. The defect was specific to skeletal muscle and heart. Stimulation of pyruvate dehydrogenase with dichloroacetate caused a 50% decrease in plasma lactate concentration but failed to improve whole-body insulin-stimulated glucose utilization in either the septic human or rat. Dichloroacetate reversed the impairment of insulin-stimulated myocardial glucose uptake in septic rats, but did not influence skeletal muscle glucose uptake either under basal conditions or during insulin stimulation. CONCLUSIONS: Activation of pyruvate dehydrogenase with dichloroacetate does not ameliorate the impairment of whole-body, insulin-stimulated glucose uptake in septic humans or rats, or reverse the specific defect in insulin-mediated skeletal muscle glucose uptake by septic rats. Therefore, the decreased pyruvate dehydrogenase activity associated with sepsis does not appear to mediate sepsis-induced insulin resistance during insulin-stimulated glucose uptake at either the whole-body or tissue level.

APACHE↗

PubMed1996

Infusion of labeled KIC is more accurate than labeled leucine to determine human muscle protein synthesis.

The leucine constant infusion method is the most commonly used method for measuring fractional synthetic rates (FSR) of muscle protein. However, this method has been criticized because of the uncertainty involved in measuring precursor pool enrichment. We present an alternative method for measuring muscle FSR by giving a constant infusion of alpha-[1-13C]ketoisocaproate (alpha-[1-13C]KIC). We infused alpha-[1-13C]KIC and [5,5,5-2H3]leucine for 4 h in five volunteers and took plasma samples half-hourly and muscle biopsies at 1 and 4 h of isotope infusion. When KIC was infused, intramuscular free leucine enrichment was the same as arterial leucine enrichment. However, when labeled leucine was infused, intramuscular free leucine enrichment was only 76 +/- 3% of arterial KIC enrichment, which agrees with previous reports that plasma KIC enrichment does not accurately reflect intramuscular leucine enrichment. We obtained an FSR of 2.25 +/- 0.12%/day by use of this method, which agrees with a previous report using tRNA bound leucine as the precursor. In conclusion, the KIC infusion method overcomes the theoretical limitations of the leucine infusion.

Carbon Isotopes↗

PubMed1996

Gut proteolysis contributes essential amino acids during exercise.

Arteriovenous difference and tracer dilution techniques were utilized to determine the effect of exercise on whole body, gut, liver, and splanchnic leucine kinetics. Five postabsorptive dogs were infused with [1-13C]leucine and studied during rest, 90 min of moderate-intensity treadmill exercise (1st 45 min, early; last 45 min, late exercise), and 90 min of recovery. The whole body leucine rate of appearance (Rai; mumol.min 1.kg-1) increased from rest (3.33 +/- 0.11) during early (3.68 +/- 0.14) and late (4.24 +/- 0.27, P < 0.05) exercise and was 3.41 +/- 0.19 during recovery. Gut Ra increased from rest (0.64 +/- 0.08) during early (0.92 +/- 0.12) and late (1.30 +/- 0.20, P < 0.05) exercise and was 0.77 +/- 0.16 during recovery. Liver leucine Ra did not significantly change (P > 0.05). The whole body leucine rate of disappearance (Rd) paralleled whole body leucine Ra throughout. Leucine Rd across the gut, liver, and splanchnic bed, however, did not significantly change (P > 0.05), indicating an increase in leucine uptake outside of these regions. Because active skeletal muscle is likely the principal consumer of these amino acids, the data suggest that gut protein-derived amino acids are utilized for the attenuation of net muscle protein catabolism during and immediately following exercise.

Amino Acids↗

PubMed1996

Prolonged bed rest decreases skeletal muscle and whole body protein synthesis.

We sought to determine the extent to which the loss of lean body mass and nitrogen during inactivity was due to alterations in skeletal muscle protein metabolism. Six male subjects were studied during 7 days of diet stabilization and after 14 days of stimulated microgravity (-6 degrees bed rest). Nitrogen balance became more negative (P < 0.03) during the 2nd wk of bed rest. Leg and whole body lean mass decreased after bed rest (P < 0.05). Serum cortisol, insulin, insulin-like growth factor I, and testosterone values did not change. Arteriovenous model calculations based on the infusion of L-[ring-13C6]-phenylalanine in five subjects revealed a 50% decrease in muscle protein synthesis (PS; P < 0.03). Fractional PS by tracer incorporation into muscle protein also decreased by 46% (P < 0.05). The decrease in PS was related to a corresponding decrease in the sum of intracellular amino acid appearance from protein breakdown and inward transport. Whole body protein synthesis determined by [15N]alanine ingestion on six subjects also revealed a 14% decrease (P < 0.01). Neither model-derived nor whole body values for protein breakdown change significantly. These results indicate that the loss of body protein with inactivity is predominantly due to a decrease in muscle PS and that this decrease is reflected in both whole body and skeletal muscle measures.

Adult↗

PubMed1996

Glucose and insulin-induced inhibition of fatty acid oxidation: the glucose-fatty acid cycle reversed.

In this study we have investigated a hypothesis that proposes the reverse of the so-called "glucose-fatty acid cycle, " i.e., that accelerated carbohydrate metabolism directly inhibits fatty acid oxidation. We studied normal volunteers in the basal state and during a hyperinsulinemic, hyperglycemic clamp (plasma insulin = 1,789 +/- 119 pmol/l, plasma glucose = 7.7 +/- 0.2 mmol/l). We quantified fat oxidation using indirect calorimetry and stable isotopes ([1-13C]oleate). Plasma oleate enrichment and free fatty acid (FFA) concentration were kept constant by means of infusion of lipids and heparin. Glucose oxidation increased from basal 6.2 +/- 0.8 to 22.3 +/- 1.4 mumol.kg-1.min-1 during the clamp (P < 0.01). Total (indirect calorimetry) and plasma fatty acid oxidation (isotopic determination) decreased from 2.6 +/- 0.2 to 0.4 +/- 0.3 (P < 0.01) and 2.2 +/- 0.2 to 1.4 +/- 0.1 mumol.kg-1.min-1 (P <0.05), respectively. We conclude that under the conditions of the present experiment, glucose and/or insulin directly inhibits fatty acid oxidation. Our findings suggest that, contrary to the prediction of the glucose-fatty acid cycle, the intracellular availability of glucose (rather than FFA) determines the nature of substrate oxidation in human subjects.

Adult↗

PubMed1996

An isotopic method for measurement of muscle protein fractional breakdown rate in vivo.

We have developed a novel method to measure the fractional breakdown rate (FBR) of muscle protein. This method involves infusing isotope tracer to reach an isotopic equilibrium and then observing its decay in the arterial blood and muscle intracellular pool. The calculation of FBR is based on the rate at which tracee released from breakdown dilutes the intracellular enrichment using a modified precursor-product equation. To test this method, L-[1,2-13C2]leucine and L-[ring-13C6]phenylalanine were infused into six dogs for measurement of FBR and fractional synthesis rate (FSR), respectively. Leucine and phenylalanine kinetics in the hindlimb were measured simultaneously using the arteriovenous (A-V) balance method. The measured FBR (0.17 +/- 0.02%/h) and FSR (0.10 +/- 0.01%/h) were in agreement with the results from the A-V balance method. In conclusion, our new method provides a feasible approach for measurement of muscle protein FBR. This method can be combined with the tracer incorporation method to measure both breakdown and synthesis in the same infusion study.

Animals↗

PubMed1996

TNF directly stimulates glucose uptake and leucine oxidation and inhibits FFA flux in conscious dogs.

We tested the hypothesis that the metabolic changes in glucose, lipid, and protein metabolism seen during tumor necrosis factor (TNF) infusion were due to the increase in plasma glucagon concentration rather than to the direct effects of TNF. We employed a pancreatic clamp technique to keep plasma insulin and glucagon concentrations constant throughout a 4-h isotope infusion. Glucose, lipid, and protein kinetics were measured by means of the primed, constant infusion of [6,6-2H]glucose, [2H5]glycerol, [2H2]palmitic acid, and [1-13C]leucine. After a 2-h baseline period (period 1), TNF was infused as a primed, constant infusion (prime, 2.5 micrograms/kg; constant infusion, 62.5 ng.kg-1.min-1) for 2 h (period 2). Whereas plasma glucose concentration dropped significantly during TNF infusion, endogenous glucose production did not change. The decrease in glucose concentrations was due to a stimulation of glucose clearance (P < 0.05). The rate of lipolysis did not decrease significantly, but free fatty acid (FFA) flux and plasma FFA concentration significantly decreased during TNF infusion (P < 0.05). The rate of appearance of leucine was not affected by TNF infusion, but TNF caused a significant increase in 13CO2 excretion (P < 0.05) and leucine oxidation (P < 0.05). The calculated rates of whole body protein synthesis decreased. We concluded that TNF did not directly affect glucose production. Furthermore, changes in protein and lipid kinetics during TNF infusion were not mediated by changes in insulin or glucagon and may have reflected direct effects of TNF.

Animals↗

PubMed1996

Response of phosphoenolpyruvate cycle activity to fasting and to hyperinsulinemia in human subjects.

We have used a new isotopic tracer technique to investigate the physiological role of the phosphoenolpyruvate (PEP) cycle in metabolic adaptation to fasting and to hyperinsulinemia. The forward direction of the PEP cycle is the conversion of oxaloacetate (OAA) to PEP, and the net flux of the cycle is the rate at which PEP from OAA goes on to form glucose or glycogen, as opposed to being recycled to pyruvate and then OAA. Normal volunteers (n = 6) were studied after an overnight fast and then again after 3 days of fasting, and five additional subjects were studied during a hyperinsulinemic clamp (insulin concentration = 568 +/- 25 microU/ml, glucose infusion = 14.2 +/- 0.55 mg.kg-1.min-1). After an overnight fast, 35.4 +/- 6.7% of PEP from OAA was recycled to pyruvate-lactate. Short-term fasting caused a significant increase in the conversion of OAA to PEP and also a drop in the percentage of PEP from OAA that went to pyruvate-lactate to 15.2 +/- 4.0%. The principal response to hyperinsulinemia was a decrease in the recycling of OAA to lactate, because there was no significant change in the conversion of OAA to PEP. We conclude that changes in both directions of the PEP cycle are important in regulating gluconeogenic-glyconeogenic flux.

Fasting↗

PubMed1996

Comparison of mass isotopomer dilution methods used to compute VLDL production in vivo.

The recent development of mass isotopomer distribution methods represents an important new tool for quantifying synthetic rates. These methods allow precursor enrichment to be determined indirectly from the enrichment of the product, thus sidestepping the often difficult problem of measuring the precursor enrichment. Two different methods have been described to compute synthetic rates by this general approach in the laboratories of M. K. Hellerstein and J. K. Kelleher, and variations of these basic approaches have also been presented by W. N. Lee and by ourselves. A comparison between the different methods has never been reported. In this paper, we take a specific application, calculation of the fractional rate of incorporation of acetyl-CoA into very low density lipoprotein-bound palmitate, and compare the results obtained from all of the mass isotopomer methods using the same data set obtained in vivo in human subjects. We found that it is critical that the measured background isotopomer distribution of palmitate is used rather than the theoretical background isotopomer distribution. We also found that the different methods give comparable precursor enrichments and comparable fractional synthesis rates, provided that the enrichments in Kelleher's method are properly weighted. Thus the choice of method to use is a matter of personal preference.

Humans↗

PubMed1996

Muscle protein metabolism in female swimmers after a combination of resistance and endurance exercise.

There is little known about the responses of muscle protein metabolism in women to exercise. Furthermore, the effect of adding resistance training to an endurance training regimen on net protein anabolism has not been established in either men or women. The purpose of this study was to quantify the acute effects of combined swimming and resistance training on protein metabolism in female swimmers by the direct measurement of muscle protein synthesis and whole body protein degradation. Seven collegiate female swimmers were each studied on four separate occasions with a primed constant infusion of ring-[13C6]phenylalanine (Phe) to measure the fractional synthetic rate (FSR) of the posterior deltoid and whole body protein breakdown. Measurements were made over a 5-h period at rest and after each of three randomly ordered workouts: 1) 4,600 m of intense interval swimming (SW); 2) a whole body resistance-training workout with no swimming on that day (RW); and 3) swimming and resistance training combined (SR). Whole body protein breakdown was similar for all treatments (0.75 +/- 0.04, 0.69 +/- 0.03, 0.69 +/- 0.02, and 0.71 +/- 0.04 mumol.min-1.kg-1 for rest, RW, SW, and SR, respectively). The FSR of the posterior deltoid was significantly greater (P < 0.05) after SR (0.082 +/- 0.015%/h) than at rest (0.045 +/- 0.006%/h). There was no significant difference in the FSR after RW (0.048 +/- 0.004%/h) or SW (0.064 +/- 0.008%/h) from rest or from SR. These data indicate that the combination of swimming and resistance exercise stimulates net muscle protein synthesis above resting levels in female swimmers.

Adult↗

PubMed1996

Regulation of the insulin-like growth factor system by insulin in burn patients.

The aim of the present investigation was to determine whether there is a net uptake of insulin-like growth factor I (IGF-I) or IGF-binding proteins (IGFBPs) by the leg after burn injury and to elucidate the regulatory role of insulin exerted on this system under in vivo conditions in burn patients. Studies were performed on nine patients after burn injury (approximately 60% body surface area). Each patient was studied twice during a continuous infusion of a carbohydrate-rich enteral diet. Blood was collected simultaneously from the femoral artery and vein for the measurement of various elements of the IGF system after 7 days of enteral diet alone (basal period) and after 7 days of the enteral diet plus the infusion of insulin (insulin period). Data from these patients were compared to values in age-matched fed healthy volunteers. During the basal period, burn patients demonstrated a significant reduction in the venous concentration of IGF-I and an increase in both IGFBP-1 and -2 compared to control values. Insulin produced a significant 15% increase in the IGF-I concentration in burn patients, but decreased the circulating levels of IGFBP-1 by 50%. The IGF-I and IGFBP-1 concentrations at the end of the insulin period were still significantly different from those in control subjects. Burn patients also exhibited a marked reduction in intact IGFBP-3 and the acid-labile subunit under basal conditions, and these alterations were not reversed by insulin. Under basal conditions, all burn patients had a positive arterio-venous (A-V) difference for IGF-I across the leg. The A-V difference was increased 50% in response to insulin. The net uptake of IGF-I by the leg was 2.4 micrograms/min under basal conditions, and as leg blood flow also tended to increase in response to insulin, IGF-I uptake was elevated more than 3-fold during the insulin period. No A-V difference across the leg was detected for IGFBP-1, -2, or -3 in burn patients. In conclusion, burn injury in humans produces dramatic and sustained alterations in various components of the IGF system that persist despite adequate nutritional support. Our data indicate the presence of a net uptake of IGF-I by the leg in burn patients that may serve to counteract the catabolic state.

Adolescent↗