The effects of infusion of insulinlike growth factor (IGF) I, IGF-II, and insulin on glucose and protein metabolism in fasted lambs.

In vivo effects of 300-min infusions of recombinant insulinlike growth factor I (IGF-I) and IGF-II on glucose and protein metabolism have been investigated in awake, fasted lambs. Two doses of recombinant human (rh) IGF-I were infused: 6.7 nmol/kg.h, which induced hypoglycemia, and 2.0 nmol/kg.h, which did not. The effects were compared with an insulin infusion (0.17 nmol/kg.h) that had the same hypoglycemic potential as the high dose rhIGF-I infusion. rhIGF-II was infused at a rate of 6.7 nmol/kg.h. Primed constant infusions of isotopically labeled glucose, urea and leucine tracers were used to determine glucose and protein kinetics. rhIGF-I lowered blood glucose by increasing the rate of glucose clearance (P less than 0.01), in contrast to insulin, which both increased clearance and reduced glucose production. Net protein loss was reduced after infusion of low and high dose rhIGF-I and insulin by 11% (P less than 0.05), 15% (P less than 0.01), and 12% (P less than 0.05), respectively. rhIGF-II infusion did not alter the rate of net protein loss. In contrast to insulin, high dose rhIGF-I infusion increased the rate of protein synthesis in skeletal (P less than 0.05) and cardiac muscle (P less than 0.01) and in hepatic tissue (P less than 0.05). We conclude that (a) protein metabolism is more sensitive than glucose metabolism to rhIGF-I infusion, as protein loss was reduced by an rhIGF-I infusion that did not alter glucose kinetics; (b) protein synthesis is increased by rhIGF-I infusion but not by insulin infusion; and (c) rhIGF-II is a less effective anabolic agent than rhIGF-I. We speculate that the effects of rhIGF-I on protein metabolism are not mediated by insulin receptors.

Role of changes in insulin and glucagon in glucose homeostasis in exercise.

This experiment was performed to determine if plasma glucose homeostasis is maintained in normal human volunteers during light exercise (40% maximal oxygen consumption [VO2 max]) when changes in insulin and glucagon are prevented. Hormonal control was achieved by the infusion of somatostatin, insulin, and glucagon. Glucose kinetics and oxidation rates were determined with stable isotopic tracers of glucose, and by indirect calorimetry. Two different rates of replacement of insulin and glucagon were used; in one group, insulin was clamped at 19.8 +/- 2.6 microU/ml (high-insulin group), and in the other group insulin was clamped at 9.2 +/- 1.3 microU/ml (low-insulin group). Glucagon was maintained at 261 +/- 16.2 and 124 +/- 6.4 pg/ml, respectively, in the high-insulin and low-insulin groups. Without hormonal control, plasma glucose homeostasis was maintained during exercise because the increase in glucose uptake was balanced by a corresponding increase in glucose production. When changes in insulin and glucagon were prevented, plasma glucose concentration fell, particularly in the high-insulin group. Glucose uptake increased to a greater extent than when hormones were not controlled, and glucose production did not increase sufficiently to compensate. The increase in glucose uptake in the hormonal control groups was associated with an increased rate of glucose oxidation. When euglycemia was maintained by glucose infusion in the hormonal control subjects, the modest increase in glucose production that otherwise occurred was prevented. It is concluded that during light exercise there must be a reduction in insulin concentration and/or an increase in glucagon concentration if plasma glucose homeostasis is to be maintained. If such changes do not occur, hypoglycemia, and hence exhaustion, may occur.

Microculture-based chemosensitivity testing: a feasibility study comparing freshly explanted human melanoma cells with human melanoma cell lines.

BACKGROUND: The culture of cancer cells has many applications in chemosensitivity testing and new drug development. PURPOSE: Our goal was to adapt simple semiautomated microculture methods for testing the chemosensitivity of melanoma cells freshly recovered from patients' tumors. METHODS: Cells were cultured on a substrate of agarose and exposed continuously to cytotoxic drugs, the effects of which were measured by determining the uptake of [3H]thymidine 4-7 days later. RESULTS: Immunocytochemical staining of cells cultured with 5-bromo-2'-deoxyuridine demonstrated that tumor cells were responsible for the measured thymidine incorporation. The effects of cytotoxic drugs were calculated as logarithmic 50% inhibitory concentrations and expressed as divergences from the mean in a log-mean graph. The inhibitory effects of amsacrine, etoposide, doxorubicin, cisplatin, mitomycin C, and fluorouracil were tested. Tumors differed widely in their sensitivity to these drugs, although sensitivity to the three topoisomerase-II-directed agents was highly correlated. Cells from two non-neoplastic hematopoietic progenitor cell lines (FT and 32D) showed chemosensitivity patterns distinct from those in the melanoma cells, indicating tissue selectivity. Two established melanoma cell lines, MM-96 and FME, were tested under the same conditions and showed sensitivity typical of at least some fresh specimens. CONCLUSIONS: These results support the validity of melanoma cell lines as models of freshly resected melanoma cells. If successfully applied to other tumor types, such semiautomated approaches could find wide application in routine hospital laboratories for the chemosensitivity testing of patients' tumor cells.

A possible role for IGE-II: evidence in sheep for in vivo regulation of IGF-I mediated protein anabolism.

Using primed constant infusions of [14C]urea we assessed the effects in castrate male lambs of insulin-like growth factor (IGF) II infusion on protein metabolism during concurrent IGF-I infusion. A 300 minute infusion of IGF-I at 15 micrograms/kg.hour (n = 4) increased (p less than 0.001) the plasma IGF-I concentration from 72.5 +/- 6.4 ng/ml to 213.6 +/- 17.4 ng/ml and decreased (p less than 0.01) the rate of net protein catabolism (NPC) from 1.48 +/- 0.28 g/kg.day to 1.02 +/- 0.18 g/kg.day. Infusion of IGF-II at a dose of 50 micrograms/kg.hour concurrently with IGF-I at 15 micrograms/kg.hour (n = 4) was associated with a similar rise (p less than 0.01) in plasma IGF-I concentration from 79.4 +/- 4.1 ng/ml to 225.2 +/- 32.8 ng/ml. Plasma IGF-II increased (p less than 0.05) from 350.6 +/- 41.6 ng/ml to 746.7 +/- 165.5 ng/ml over the infusion. Coadministration of IGF-II completely blocked (p less than 0.01) the anabolic effect of IGF-I and the rate of NPC remained unchanged throughout the combined IGF-I and IGF-II infusion at a level comparable to saline infused controls (n = 4). This study suggests that IGF-II may play a physiological role as a circulating modulator of the anabolic effects of IGF-I.

Synergistic effect of insulin-like growth factor-I administration on the protein-sparing effects of total parenteral nutrition in fasted lambs.

Using primed constant isotopic infusions, we investigated the effects of recombinant human insulin-like growth factor-I (IGF-I) infusion on protein kinetics in both fasted and parenterally fed (TPN) lambs. Infusion of IGF-I at a dose of 50 micrograms/kg.h in fasted animals increased (P less than 0.005) the mean plasma IGF-I concentration from 77.5 +/- 9.7 to 454.4 +/- 51.4 ng/ml. During IGF-I infusion the rate of net protein catabolism (NPC) was decreased (P less than 0.005) by 17% from 3.5 +/- 0.2 to 2.9 +/- 0.2 g/kg.day, and the rate of appearance (Ra) of leucine in plasma decreased (P less than 0.01) from 5.0 +/- 0.4 to 3.4 +/- 0.4 mumol/kg.min. In addition, the fractional synthetic rate of protein in cardiac and diaphragmatic muscle increased by 100% (P less than 0.05) during the same period. After 3 h of TPN, the rate of NPC was decreased (P less than 0.01) in the TPN animals compared to that in their fasted counterparts (1.89 +/- 2.27 vs. 4.1 +/- 0.2 g/kg.day, respectively). The rate of NPC was further decreased after another 300 min of TPN to 0.76 +/- 0.27 g/kg.day. However, the Ra of leucine was not changed compared to the initial value. Infusion of IGF-I concurrently with TPN reversed (P less than 0.001) the rate of NPC from 1.02 +/- 0.21 g/kg.day after 180 min of TPN alone to a state of net protein gain of 0.14 +/- 0.19 g/kg.day after a further 300 min of combined IGF-I and TPN infusion. The Ra of leucine decreased (P less than 0.01) from 3.9 +/- 0.8 to 2.5 +/- 0.47 mumol/kg.min during IGF-I and TPN infusion. Similarly, the fractional synthetic rates of protein in cardiac muscle, diaphragm, adductor muscle, psoas muscle, and hepatic tissue were increased (P less than 0.05) compared to those in animals that received only TPN. The protein-sparing effects of IGF-I and TPN were synergistic, and the infusion of both agents resulted in the induction of a protein anabolic state within 60 min of commencing IGF-I infusion. In contrast, neither IGF-I nor TPN alone resulted in a state of net protein anabolism, and neither had an effect on protein kinetics until 120 min into the infusion. Consequently, IGF-I shows considerable potential as an anticatabolic agent when used synergistically with nutritional support.

Influence of stress, depletion, and/or malignant disease on the responsiveness of surgical patients to total parenteral nutrition.

We performed a series of 14C[urea] infusions to assess the effect of depletion (greater than 15% decrease in body weight), stress (VO2 greater than 130 mumol.kg-1.min-1), and cancer on the basal rate of net protein catabolism (NPC) and the response of patients to total parenteral nutrition (TPN). Depleted patients had low rates of NPC (0.8 +/- 0.1 g.kg-1.d-1) compared with nondepleted patients (p less than 0.05) and during TPN anabolism was achieved (0.5 +/- 0.2 g.kg-1.d-1). Gastrointestinal (GI) cancer patients had rates of NPC similar to those of normal volunteers; during TPN, NPC approximated zero. Severely stressed (SS) nondepleted patients had high rates of NPC (2.7 +/- 0.2 g.k-1.d-1) whereas SS-depleted patients had lower (p less than 0.05) rates of NPC (1.9 +/- 0.3 g.kg-1.d-1); both groups of SS patients remained catabolic despite TPN (1.2 +/- 0.3 and 0.5 +/- 0.2 g.kg-1.d-1, respectively). In response to TPN, depleted patients become anabolic, GI cancer patients stop losing protein but do not become anabolic, and stressed patients remain catabolic and continue to loss protein.

Spinocerebellar ataxia type 2: clinical features of a pedigree displaying prominent frontal-executive dysfunction.

BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) is a recently delineated cause of autosomal dominant cerebellar ataxia type I. The basic clinical neurologic features of SCA2 have been described in the literature, but neuropsychological features have not, despite statements that some patients became demented. OBJECTIVE: To describe the clinical and neuropsychological features of patients from a pedigree with SCA2. PATIENTS AND METHODS: We studied 8 affected members of an Australian pedigree of northern Italian origin with autosomal dominant cerebellar ataxia type I caused by SCA2. Patients underwent clinical neurologic examination and abbreviated neuropsychological testing, while some also underwent magnetic resonance imaging. The results were compared with pooled results from previously published studies of patients with SCA2. RESULTS: The pedigree displayed anticipation, with earlier onset in later generations, and there was an inverse correlation between repeat number and age at onset. The principal difference from other clinical reports of SCA2 was our finding of unequivocal frontal-executive dysfunction in 5 of 6 individuals who could be tested quantitatively, despite Mini-Mental State Examination scores in the nondemented range. This feature did not appear to correlate with either repeat size or duration of illness. CONCLUSIONS: In light of a recent report of frontal-executive dysfunction in spinocerebellar ataxia type III, we postulate that this pattern may be common to the autosomal dominant cerebellar ataxias and frequently may be overlooked because of the insensitivity of routine screening tests such as the Mini-Mental State Examination.

Radiosensitivity of new and established human melanoma cell lines: comparison of [3H]thymidine incorporation and soft agar clonogenic assays.

Seven new low-passage melanoma lines were developed in this laboratory from clinical melanoma specimens and characterised for chromosome complement, DNA ploidy and S-phase content. The radiosensitivity of these lines was compared with that of eight established melanoma cell lines, FME, MM-96, SK-MEL-5, SK-MEL-28, SK-MEL-2, MALME-3M, M19-MEL and LOX-IMVI, using a 96-well microculture assay technique. Dose-response curves were determined using a 5-day incubation period and 6-h terminal [3H]thymidine-labelling period. Radiation (60Co source) was carried out under a lead wedge to provide a radiation dose range of 0-10 Gy, or by irradiating part of the plate (radiation dose 0 or 2 Gy). Data for a range of cell densities in a single 96-well plate were combined into a single regression equation incorporating linear quadratic terms for radiation dose and cell density. SF2 values were defined as the amount of thymidine incorporated following a radiation dose of 2 Gy, expressed as a fraction of that of unirradiated cells, and varied from 0.36 to 0.93. The reproducibility in repeat assays, as defined by the standard error of determinations at different passage numbers, was +/- 0.04. The newly developed lines exhibited a similar range of radiosensitivity to that of the established lines, and melanin content did not correlate with resistance. For nine of the lines, radiation parameters were also determined using a modified Courtenay clonogenic soft agar assay technique, and the results compared with the thymidine incorporation results, and a significant linear correlation was found between SF2 and SF2' (r = 0.89). The linear (alpha) and quadratic (beta) terms of the best-fit linear quadratic dose-response curves, were significantly correlated between the two assays. It is concluded for this series of human melanoma lines that proliferation assays in 96-well plates provide radiosensitivity parameters comparable to those using clonogenic assays.

Passive immunization against circulating insulin-like growth factor-I (IGF-I) increases protein catabolism in lambs: evidence for a physiological role for circulating IGF-I.

Primed constant infusions of [14C]urea were used to determine the acute effect of passive immunization against circulating free and protein-bound insulin-like growth factor-I (IGF-I) on the rate of net protein catabolism (NPC) in castrated male lambs fasted for 48 h. Following an intravenous bolus of 50 ml IGF-I antiserum, the rate of NPC increased to a peak 30 min after injection of 1.69 +/- 0.16 g/kg per day from a baseline value of 1.45 +/- 0.22 g/kg per day (P < 0.05, n = 4). In three animals given 50 ml equivalents of the purified immunoglobulin fraction, NPC increased from 1.31 +/- 0.20 to 1.59 +/- 0.16 g/kg per day (P < 0.05). A similar trend was observed in animals given 25 ml antiserum (n = 4). The rate of NPC did not increase following a bolus of non-immune serum in control animals and the rate of NPC in the treated lambs returned to control levels within 60 min of antibody injection. Plasma insulin and glucose concentrations in both the treated and control groups were unchanged throughout the study. These data suggest that circulating IGF-I has a physiological role in regulating whole body protein turnover during starvation and possibly other catabolic states. The effect of immunoneutralization of circulating IGF-I is transient and this suggests that while IGF-I has an endocrine role in the regulation of protein turnover, other regulatory mechanisms are involved.

Frequency of spinocerebellar ataxia types 1, 2, 3, 6, and 7 in Australian patients with spinocerebellar ataxia.

The frequencies of various genetically defined spinocerebellar ataxias (SCAs) vary in different populations presumably due to founder effects. No data have been published on the Australian population. Although predominantly of Anglo-Celtic extraction, Australia has also received considerable influx from southeastern Europe and more recently eastern and southeastern Asia. We examined the frequency of mutations for SCA types 1, 2, 3, 6, and 7 in southeastern Australia. Of 88 pedigrees with multiple-affected members, SCA type 1 (SCA1) accounted for 16%, SCA2 for 6%, SCA3 for 12%, SCA6 for 17%, SCA7 for 2%, and 47% (41 pedigrees) were negative for each of SCA1, 2, 3, and 6. Twenty of the 41 negative pedigrees were also negative for dentatorubralpallidoluysian atrophy, and indeed dentatorubralpallidoluysian atrophy has not been reported in Australia. In addition, no pedigree information was available on a further four patients with SCA1, three patients with SCA2, three patients with SCA3, and three patients with SCA6. One SCA1 and two SCA2 patients had no other known affected family members. In total, of 63 pedigrees or individuals with positive tests, 30% were those with SCA1, 15% with SCA2, 22% with SCA3, 30% with SCA6, and 3% with SCA7. Judging by pedigree names, four of the nine SCA2 positive individuals/pedigrees were of Italian extraction, and four of the 14 SCA3 positive individuals/pedigrees were of Chinese descent, whereas only 1 of the 20 SCA1 positive individuals/pedigrees were non-Anglo-Celtic. These results are in accordance with the known ethnic composition of the Australian population and with gene frequencies in these constituent ethnic groups reported by others. The frequency of large-normal alleles for SCA1 and SCA3 in the population reflects the prevalence of these two diseases, supporting the hypothesis that disease alleles arise by expansion of large-normal alleles.

Whole-body protein kinetics in patients with early and advanced gastrointestinal cancer: the response to glucose infusion and total parenteral nutrition.

We have isotopically determined rates of whole-body protein synthesis and catabolism in a group of normal volunteers and in two groups of cancer patients: 20 patients with advanced weight-loss (AWL) upper gastrointestinal cancer and 7 patients with early non-weight-loss (ENWL) lower gastrointestinal cancer. In both patients and volunteers we determined protein kinetics in the basal state and during glucose infusion at 4 mg/kg/min. In addition, in the AWL patients the effect of total parenteral nutrition (TPN) on protein dynamics was also assessed. The rate of net protein breakdown was determined with the primed constant infusion of either 15N-urea or 14C-urea, the rate of whole-body protein catabolism was measured with the primed constant infusion of 15N-lysine, and the rate of whole-body protein synthesis was deduced from the above two values. The basal rates of net protein catabolism, whole-body protein catabolism, and whole-body protein synthesis were similar in the volunteers and ENWL cancer patients. The basal values for net protein catabolism in the volunteers and ENWL patients were 1.46 +/- 0.18 and 1.34 +/- 0.08 gm/kg/min, respectively. In both volunteers and ENWL patients glucose infusion resulted in a significant decrease in net protein catabolism. In the ENWL patients this decrease was due to a significant decrease in whole-body protein catabolism (p less than 0.05); the rate of whole-body protein synthesis did not change significantly. In the AWL cancer patients the rate of net protein catabolism was significantly higher than in either the volunteer or ENWL group (p less than 0.05), and glucose infusion did not result in a decrease in net protein catabolism. However, when the AWL group was studied during TPN there was a significant decrease in net protein catabolism from 2.24 +/- 0.30 to 0.17 +/- 0.09 gm/kg/day (p less than 0.01). This decrease was due to the combined effect of a significant decrease in whole-body protein catabolism coupled with an increase in whole-body protein synthesis. From these studies we conclude the following: (1) ENWL cancer patients and normal volunteers have similar protein dynamics, and in both groups glucose infusion resulted in a significant decrease in protein loss. (2) AWL cancer patients have an elevated rate of net protein catabolism, and this is not sensitive to glucose infusion.(ABSTRACT TRUNCATED AT 400 WORDS)

Glucose and urea kinetics in patients with early and advanced gastrointestinal cancer: the response to glucose infusion, parenteral feeding, and surgical resection.

We isotopically determined rates of glucose turnover, urea turnover, and glucose oxidation in normal volunteers (n = 16), patients with early gastrointestinal (EGI) cancer (n = 6), and patients with advanced gastrointestinal (AGI) cancer (n = 10). Studies were performed in the basal state, during glucose infusion (4 mg/kg/min), and during total parenteral feeding (patients with AGI cancer only). Patients with early stages of the disease were also studied 2 to 3 months after resection of the cancer. Basal rates of glucose turnover were similar in volunteers and in patients with EGI cancer (13.9 +/- 0.3 mumol/kg/min and 13.3 +/- 0.2 mumol/kg/min, respectively) but were significantly higher in patients with AGI cancer (17.6 +/- 1.4 mumol/kg/min). Glucose infusion resulted in significantly less suppression of endogenous production in both patient groups than that seen in the volunteers (76% +/- 6% for EGI group, 69% +/- 7% for AGI group, and 94% +/- 4% for volunteers). The rate of glucose oxidation increased progressively in proportion to the tumor bulk. In the volunteers the percent of VCO2 from glucose oxidation was 23.9% +/- 0.7%, and in EGI and AGI groups the values were 32.8% +/- 2.0% and 43.0% +/- 3.0%, respectively. After curative resection of the cancer, glucose utilization decreased significantly (p less than 0.05). The rate of urea turnover was significantly higher in the AGI group (8.4 +/- 1.0 mumol/kg/min) in comparison with the volunteer group value of 5.9 +/- 0.6 mumol/kg/min (p less than 0.03). Glucose infusion resulted in a significant suppression of urea turnover in the volunteers (p less than 0.02), but in the AGI group glucose infusion did not induce a statistically significant decrease. We conclude from these studies that the presence of even a small, potentially curable gastrointestinal cancer is associated with a loss of the normal host-regulatory mechanisms designed to conserve body resources; this effect is more marked as the tumor bulk increases; increasing tumor bulk effects a progressive increase in glucose utilization and in protein breakdown.

A conscious septic dog model with hemodynamic and metabolic responses similar to responses of humans.

We have developed a conscious septic dog model suitable for in vivo tracer studies. Dogs weighing 10 to 20 kg underwent general anesthesia followed by the insertion of long-term arterial, venous, and portal cannulas and the formation of a long-term tracheostomy. After 7 to 10 days of convalescence, the animals were fed in the morning and 4 hours later 10(10) live Escherichia coli organisms were infused intra-arterially over approximately 30 minutes. One hour later a second dose of 5 X 10(9) bacteria was given, again over 30 minutes. Resuscitation was provided by infusion of 1000 ml of lactated Ringer solution over 3 hours. Twenty-four hours after the induction of sepsis the animals were hemodynamically stable and suitable for study. Cardiac output was increased from the control value of 185 +/- 35 ml/kg X min to 308 +/- 44 ml/kg X min in the septic animals. Heart rate was increased from 98 +/- 10 to 125 +/- 5 beats/min, and arterial pressure was not significantly altered. We employed indirect calorimetry and primed constant infusions of both radioactive and stable isotopes to assess a variety of metabolic parameters. The metabolic rate was increased approximately 25%, and the energy for this increase was primarily provided by the increased oxidation of both free fatty acids and triglyceride. The release of free fatty acids was approximately three times greater than the control value, and triglyceride synthesis increased 500%. The oxidation rate of free fatty acids and the fatty acids contained in very low density lipoproteins-triglyceride increased 40% and 900%, respectively. Glucose production was maintained at approximately the control value, and the rate of glucose oxidation (as measured with 14C-glucose) was also not significantly altered. The plasma insulin concentration was moderately elevated, and plasma glucagon concentration was five to six times greater than the control value. Plasma catecholamine levels were increased significantly. This model is suitable for the performance of metabolic studies in sepsis. The induction of a hyperdynamic septic state in less than 24 hours avoids the complications of starvation and dehydration frequently seen in the various peritonitis and abscess models. Most importantly, the model is predictable in its time course and reproducibly creates a situation that hormonally, hemodynamically, and metabolically resembles what is commonly seen in humans with sepsis.

Assessment of alanine, urea, and glucose interrelationships in normal subjects and in patients with sepsis with stable isotopic tracers.

The kinetic interactions among glucose, alanine, and urea metabolism were studied in both normal volunteers and in patients with sepsis by means of a primed, constant infusion of stable isotopes. In the normal volunteers, infusion of glucose at 4 mg/kg/min suppressed total glucose production, the rate of gluconeogenesis from alanine, and the production of urea, despite an increase in the rate of release and uptake of alanine. When the glucose infusion rate was increased to 8 mg/kg/min, the production of urea decreased further, even though gluconeogenesis from alanine was already suppressed by the first infusion. This additional N-sparing effect was explainable by an increase in glucose oxidation. In the patients with sepsis the basal rates of production of glucose and urea were elevated significantly. Glucose infusion (4 mg/kg/min) decreased hepatic glycogenolysis but not gluconeogenesis from alanine or urea production. At the glucose infusion rate of 8 mg/kg/min, glucose oxidation increased in the patients and urea production decreased. Thus in patients with sepsis a higher rate of glucose infusion is necessary to achieve nitrogen-sparing effects than is necessary in controls because of a lack of suppressibility of gluconeogenesis. Because of continued glucose production during glucose infusion, hyperglycemia commonly develops during glucose infusion in sepsis. However, this effect does not necessarily indicate a complete inability of the patient with sepsis to benefit nutritionally from infused glucose, as we observed no decrement in the ability to oxidize infused glucose.

Leucine kinetics in patients with benign disease, non-weight-losing cancer, and cancer cachexia: studies at the whole-body and tissue level and the response to nutritional support.

We have performed intraoperative isotopic infusions of carbon 14-labeled leucine in 65 patients to define the abnormalities in protein metabolism at both the whole-body and tissue level in patients with weight-losing and non-weight-losing cancer. Eighteen patients had benign disease, 26 had non-weight-losing cancer, and 21 had cancer cachexia. Samples of plasma and expired breath were taken to determine rates of whole-body protein synthesis (WBPS), whole-body protein catabolism (WBPC), net protein catabolism, and albumin fractional synthetic rates. Tissue samples were taken to determine the fractional synthetic rates (FSR) of protein in muscle, liver, cancer, and the tissue in which the cancer arose. In addition, in 14 patients the effect of nutritional support on protein metabolism was assessed. In all parameters examined we were unable to detect any significant differences between patients with no cancer and the patients with non-weight-losing cancer. In contrast, patients with cancer cachexia had a significant elevation (p less than 0.005) in WBPC compared with the other two groups. WBPS was also elevated (to a lesser extent) in the patients with cancer cachexia, and the rate of net protein catabolism was increased significantly (p less than 0.05). Patients with cancer cachexia also had significantly higher values of FSR of protein in muscle (p less than 0.05), liver (p less than 0.05), and albumin (p less than 0.01) compared with the other two groups. In addition, the protein FSR in the cancer rose progressively when the values for the primary cancer were compared with those for nodal and systemic metastases. Further, although nutritional support resulted in an increase in host muscle protein synthesis (p less than 0.04), there was no promotion of FSR of protein in cancer. We conclude that patients with cancer cachexia are actively losing protein as a result of an increase in WBPC that is only partially compensated for by an increase in WBPS. There are compensatory increases in protein synthesis in muscle and liver, but these increases in host protein synthesis are insufficient to keep pace with the combined effect of the accelerated rate of protein synthesis in the cancer per se and the accelerated rate of net protein catabolism at the whole-body level. In response to nutritional support, there is a significant increase in the muscle protein synthesis, but we could not demonstrate any increase in cancer protein synthesis.

Total energy expenditure during total parenteral nutrition: ambulatory patients at home versus patients with sepsis in surgical intensive care.

BACKGROUND: To avoid the complications associated with overfeeding or underfeeding, the energy requirements of patients receiving total parenteral nutrition (TPN) must be accurately prescribed. However, until recently it has not been possible to directly measure the rates of total energy expenditure (TEE) in surgical patients receiving TPN. METHODS: Values for total body water and TEE in four patients with sepsis (mean Acute Physiology and Chronic Health Evaluation [APACHE] score, 10) receiving TPN in surgical intensive care unit and in four patients with chronic intestinal failure receiving long-term TPN at home (HPN) have been determined by using the doubly labeled water technique. The values for TEE have been compared with those of resting energy expenditure obtained with indirect calorimetry (REE CAL) and calculated by using the Harris-Benedict equation (REE HB). RESULTS: In both the patients with sepsis and the patients receiving HPN the proportion of body weight made up of water was normal for patient age and gender. In patients with sepsis the REE HB significantly (p < 0.05) underestimated the REE CAL (15.39 +/- 3.80 kcal/kg/day-1 versus 31.3 +/- 1.23 kcal/kg/day-1) and was significantly less than the TEE derived by using doubly labeled water (44.62 +/- 1.09 kcal/kg/day-1; p < 0.001). In the ambulatory patients receiving HPN no difference was noted between the REE HB and the REE CAL (18.02 +/- 0.41 kcal/kg/day-1 versus 21.37 +/- 0.94 kcal/kg/day-1). The average TEE for these patients was 30.25 +/- 3.42 kcal/kg/day-1, and this was significantly greater (p < 0.006) than both REE CAL and REE HB: CONCLUSIONS: This investigation has shown that in patients with sepsis TEE constitutes 1.4 times the REE CAL or approximately 40 kcal/kg/day, whereas in HPN patients TEE can be estimated by supplying 1.4 times the REE or approximately 30 kcal/kg/day-1.

Metabolic intervention in surgical patients: the effect of alpha- or beta-blockade on glucose and protein metabolism in surgical patients receiving total parenteral nutrition.

We performed a series of isotopic studies on the role of alpha- or beta-adrenergic activity in the regulation of glucose and protein metabolism in a group of surgical patients receiving total parenteral nutrition. We quantitated rates of glucose turnover and net protein breakdown by the primed constant infusion of 3H-glucose and 14C-urea, respectively. Basal measurements were first performed, and then the effect of either alpha- or beta-adrenergic blockade was assessed by means of the constant infusion of either phentolamine or propranolol. In addition, we assessed the effect of beta-stimulation by infusing the beta-agonist, salbutamol. The institution of alpha-adrenergic blockade did not significantly alter either the plasma glucose level or the rate of glucose production. However, the rate of net protein catabolism decreased significantly after alpha-adrenergic blockade. Before alpha-blockade the value for NPC was 0.88 +/- 0.27 gm/kg/day, and after alpha-blockade the corresponding value was 0.73 +/- 0.24 gm/kg/day (p less than 0.01). beta-Adrenergic blockade resulted in a decrease in the rate of glucose appearance from 38.2 +/- 6.1 mumol/kg/min to 35.1 +/- 5.7 mumol/kg/min, and the plasma glucose clearance increased from 5.0 +/- 0.8 ml/kg/min to 5.4 +/- 0.8 ml/kg/min. As a result of these changes the plasma glucose concentration decreased significantly (p less than 0.01) from 7.4 +/- 0.3 mumol/ml to 6.5 +/- 0.5 mumol/ml. beta-Adrenergic blockade did not significantly decrease the rate of net protein catabolism. beta-Stimulation with salbutamol resulted in a significant increase (p less than 0.05) in the rate of glucose production from 31.3 +/- 4.2 mumol/kg/min to 38.0 +/- 6.5 mumol/kg/min, and as a result the plasma glucose level increased significantly from 6.7 +/- 0.6 mumol/ml to 7.4 +/- 0.6 mumol/ml (p less than 0.04). We conclude from these studies that the role of the adrenergic nervous system in the promotion of endogenous glucose turnover in surgical patients receiving total parenteral nutrition is primarily a beta-adrenergic effect, whereas the promotion of protein catabolism is mainly an alpha-adrenergic effect.

Glucose, fat, and protein kinetics in patients with primary and secondary hyperparathyroidism.

We performed a series of isotopic studies in 16 normal volunteers, four patients with secondary hyperparathyroidism (SHPT), and in nine patients with primary hyperparathyroidism (PHPT). Using the primed constant infusion of stable and radioisotopes, we have determined glucose, glycerol, free fatty acids, and urea kinetics, as well as glucose oxidation. Measurements were performed both in the basal state and during glucose infusion (4 mg/kg body weight/min). Compared with normal volunteers, PHPT patients are intolerant of glucose because of a limited suppression of endogenous glucose turnover during glucose infusion (34% versus 96% suppression). In addition, the plasma cortisol level increased in the PHPT patients during glucose infusion. Glucose oxidation and fat kinetics in both PHPT patients and volunteers were similar, but the rate of net protein loss was significantly greater in the PHPT patients than in the volunteers (2.1 +/- 0.5 versus 1.4 +/- 0.2 gm/kg/day). Rates of VO2 in the PHPT patients and volunteers were similar, but the value in the SHPT patients was higher (120 +/- 9 versus 142 +/- 20 mumol/kg/min for PHPT and SHPT patients, respectively). The SHPT patients had significantly increased rates of glucose turnover, glucose clearance, and glycerol turnover, compared with the other two groups, as well as an increased reliance on glucose for energy. We conclude from these studies that (1) SHPT patients are catabolic and have increased rates of glucose and fat turnover; (2) PHPT patients have limited suppression of endogenous glucose turnover after glucose infusion compared with volunteers and higher rates of net protein loss; (3) fat metabolism and glucose utilization are unimpaired in PHPT patients; and (4) these alterations in metabolism and hormonal response to glucose infusion suggest that some of the symptoms seen in these patients may have a metabolic-hormonal basis.

Effect of epinephrine infusion and adrenergic blockade on glucose oxidation in conscious dogs.

The effect of combined alpha- and beta-adrenergic blockade, and the effect of epinephrine infusion, on the rate of glucose oxidation has been tested in conscious dogs. The dogs were prepared seven to ten days before the experiment with chronic catheters and tracheostomy. Glucose oxidation was measured by means of the primed-constant infusion of U-14C-glucose and indirect calorimetry. Six experimental groups were tested. In all groups, insulin and glucagon concentrations were held constant throughout by the inhibition of their secretion with somatostatin and intraportal replacement at basal rates. All experiments consisted of two two-hour periods. In half of the experiments, combined alpha- and beta-adrenergic blockade was administered in the second period, and in the other experiments, epinephrine was infused in the second period. The adrenergic blockade or epinephrine infusion (E) was performed in three different groups. In one, free fatty acid (FFA) levels were allowed to change spontaneously in response to blockade or E; in a second group, liposyn and heparin were infused throughout periods 1 and 2 in order to maintain FFA levels at high, constant levels; and in a third group, FFA levels were maintained at a constant low level in periods 1 and 2 by means of an infusion of nicotinic acid. In all cases tested, epinephrine infusion caused an increase in the rate of glucose oxidation. Adrenergic blockade also caused an increase in glucose oxidation when FFA levels were allowed to spontaneously fall; but when FFA levels were held constant (either high or low), there was no effect on glucose oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)

Response to glucose and lipid infusions in sepsis: a kinetic analysis.

The kinetics and oxidation of glucose and free fatty acid (FFA) metabolism were assessed in control and Escherichia coli septicemic dogs by using primed, constant infusions of U-14C-glucose and 1,2, 13C-palmitic acid. In the controls, the infusion of glucose suppressed endogenous glucose production completely, whereas, in the septic dogs, only a 30% suppression of glucose production occurred. The ability of the septic dogs to oxidize endogenous or exogenous glucose was decreased significantly. The basal rate of appearance of FFA was significantly higher in the septic dogs, but their ability to oxidize FFA was comparable to that of the control dogs; therefore, the basal rate of FFA oxidation was higher in the septic dogs. These studies indicate that septic dogs have a decreased capacity to oxidize glucose, but that they retain their ability to oxidize long-chain fatty acids. Because the rate of lipolysis was increased in sepsis, lipid was the predominate energy substrate in this septic model.