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Biomedical subjects

D Halliday

Publications and source records attributed to D Halliday.

At least 91 records · Page 5Linked to original sources
PubMed1989

Failure of insulin infusion to stimulate fractional muscle protein synthesis in type I diabetic patients. Anabolic effect of insulin and decreased proteolysis.

We evaluated the influence of insulin on fractional mixed skeletal muscle protein synthesis (FMPS) in eight type I (insulin-dependent) diabetic patients in the postabsorptive state. FMPS was calculated from the increment in [13C]leucine in mixed skeletal muscle protein obtained by serial percutaneous needle biopsy during a continuous 8-h intravenous infusion of L-[13C]leucine. We used the plasma [13C]-alpha-ketoisocaproate (representing intracellular leucine labeling) as the precursor pool of protein synthesis for our calculations. FMPS during the insulin treatment (0.0472 +/- 0.0046%/h; plasma glucose 4.6 +/- 1.0 mM) was not different from FMPS during insulin deprivation (0.0499 +/- 0.0046%/h; plasma glucose 16.4 +/- 0.5 mM). Using plasma [13C]-alpha-ketoisocaproate at isotopic plateau for calculation of leucine flux and as the precursor for leucine oxidation, we further confirmed the findings of our group and others that insulin treatment decreases leucine flux, leucine oxidation, and the nonoxidative portion of leucine flux. Our data on direct measurement of FMPS provide further evidence that the anabolic effect of insulin in the postabsorptive type I diabetic patient is mediated via reduction of proteolysis rather than by increasing protein synthesis.

Adult↗
PubMed1989

Antibodies in rheumatoid arthritis react specifically with the glycine alanine repeat sequence of Epstein-Barr nuclear antigen-1.

Antibodies to rheumatoid arthritis nuclear antigen (RANA) are four- to sixfold increased in sera from patients with rheumatoid arthritis (RA), whereas levels of antibodies to other EBV encoded antigens are slightly elevated or normal. We have demonstrated that the major epitopes recognised by anti-RANA antibodies are represented by a synthetic peptide, P62, corresponding to part of the internal repeat sequence which contains only the amino acids glycine and alanine. In an enzyme-linked immunosorbent assay, anti-P62 antibodies in rheumatoid arthritis sera were four fold higher than healthy and disease controls. By contrast, levels of antibodies to a cloned fusion protein, representing the C-terminus of EBNA-1 and excluding the IR3 region, were normal in RA, but elevated fivefold in nasopharyngeal carcinoma (NPC). Affinity purified anti-P62 antibodies reacted with EBNA-1 and RANA but also with a 60 kD protein present in tissue extracts which has been tentatively identified as cytokeratin. This suggests that the specific increase of anti-P62 antibodies in RA may be due to cross-reactions with autoantibodies to structural proteins with repeat sequences containing glycine. Such sequences are found in cytokeratin and proteoglycans, suggesting that anti-P62 (and hence anti-RANA) antibodies may be cross-reactive antibodies of pathogenic significance in RA, though not necessarily indicating an aetiological role for EBV.

Alanine↗
PubMed1989

Effect of triiodothyronine on leucine kinetics, metabolic rate, glucose concentration and insulin secretion rate during two weeks of fasting in obese women.

We investigated the effect of the fasting-induced reduction in triiodothyronine (T3) on metabolic changes that occur during fasting. In five obese women (T3 group) the serum T3 level during a 2200 kcal/day diet was 3.34 +/- 0.23 nmol/l while taking 20 micrograms T3 8-hourly, 0.65 +/- 0.04 after one week of fasting while not taking T3, and 2.9 +/- 0.3 after a second week of fasting while taking T3 20 micrograms 8-hourly. In three other obese women (control group) who did not take T3, T3 concentrations decreased during fasting and remained low at the end of both the first and second week of fasting. In the T3 group, resting metabolic rate (RMR) (O2 ml/min) decreased 11.7 percent at the end of one week of fasting, but then increased by 5.3 percent at the end of the second week of fasting, whereas in the control group RMR decreased by 13.1 percent after one week of fasting and a further fall of 13.3 percent occurred by the end of the second week of fasting. The RMR at the end of 2 weeks of fasting of the control group was significantly lower (P less than 0.05) than predicted using the equation of Dore, whereas that of the T3 group was as predicted using the same equation. The changes in leucine flux, leucine oxidation and non-oxidative portion of leucine flux were not different during fasting between the T3 group and the control group. Plasma concentrations of glucose, insulin and C-peptide increased from the end of one week of fasting to the end of 2 weeks of fasting in the T3 group, whereas they decreased in the control group. It is concluded that the changes in T3 concentration during fasting affected RMR, glucose metabolism and insulin secretion but failed to influence leucine metabolism.

Adult↗
PubMed1988

Postoperative positive nitrogen balance with intravenous hyponutrition and growth hormone.

11 patients having major gastrointestinal surgery were allocated at random to receive either biosynthetic human growth hormone (BSHGH) 0.1 mg/kg or placebo daily for the first 7 postoperative days. All patients received the same intravenous feeding regimen, which contained 2.09 MJ glucose, 1.88 MJ fat, and 7 g N daily. Patients receiving BSHGH were in positive nitrogen balance throughout the study (mean 1.8 [SEM 0.4] g N/day) and those receiving placebo were in negative nitrogen balance (mean -0.9 [0.7] g N/day). Resting energy expenditure progressively increased in the patients receiving BSHGH (115.7% [14.8] on day 7) but remained unchanged in patients receiving placebo (99.35% [1.4]). Fat oxidation was nearly three times higher in the patients on BSHGH (4.09 [0.38] MJ/day) than in controls (1.38 [0.50]). Carbohydrate oxidation remained about the same in both groups. Whole-body protein turnover, synthesis, and breakdown were increased in the patients receiving growth hormone.

Aged↗
PubMed1988

Rate of protein synthesis in skeletal muscle of normal man and patients with muscular dystrophy: a reassessment.

1. Quadriceps muscle protein synthetic rate has been determined in healthy subjects in the post-absorptive (n = 18) and fed (n = 10) states and in patients with a variety of myopathies, by analysis of the enrichment of serial muscle biopsies taken during primed continuous infusion of L-[1-13C]leucine. 2. Quadriceps protein synthetic rates in normal subjects were (mean +/- SD) 0.046 +/- 0.012 and 0.075 +/- 0.014%/h in the post-absorptive and fed states respectively. These results are significantly lower than we previously reported (M. J. Rennie et al., Clinical Science, 1982, 63, 519-523 [1]) but show the same relative differences of direction and magnitude, confirming the effects of feeding previously reported. In patients with muscular dystrophy, muscle protein synthetic rate was, as previously reported [1], much lower in the fed state than in normal subjects. A new finding is that for patients with myotonic dystrophy the rate is also depressed in the post-absorptive state. 3. We suggest that the present estimates in post-absorptive and fed normal subjects be used as reference values for quadriceps mixed muscle protein synthetic rate.

Adult↗
PubMed1988

Influence of amino acid administration on whole-body leucine kinetics and resting metabolic rate in postabsorptive normal subjects.

1. We have investigated the effect of an amino acid mixture (Vamin 14; 57.4 +/- 10.2 mumol h-1 kg-1) on whole-body leucine kinetics, calculated by a steady-state reciprocal pool model, and resting metabolic rate in eight postabsorptive normal subjects. 2. Vamin 14 infusion increased whole-body leucine flux (P less than 0.001), leucine employed for protein synthesis (P less than 0.001), leucine oxidation (P less than 0.001), metabolic clearance rate of alpha-ketoisocaproic acid (P less than 0.05) and levels of all three branched-chain amino acids (P less than 0.001) compared with the basal situation. In contrast, whole-body proteolysis was reduced (P less than 0.05). 3. Resting metabolic rate was increased during Vamin 14 infusion (P less than 0.05) and was positively correlated with whole-body protein synthesis (n = 16, r = 0.6342, P less than 0.01; y = 0.605x + 173.7), as was the change in metabolic rate with the change in protein synthesis (n = 8, r = 0.772, P less than 0.05; y = 0.493x - 10.85). 4. Overall, Vamin 14 infusion was associated with increased blood glucose (P less than 0.001), although the observed increase in plasma glucagon (t = 2.012) and plasma insulin (t = 1.683) failed to reach statistical significance. 5. These data lend a measure of support to the hypothesis that the apparent increase in whole-body protein synthesis in insulin-dependent diabetic (type I) subjects during insulin withdrawal may be substrate related.

Adult↗
PubMed1988

Effect of gut-derived acetate on glucose turnover in man.

1. The effect of acetate absorbed from the gut on glucose turnover has been determined in four healthy subjects during both fasting and an intravenous glucose infusion by using [U-13C]glucose. 2. In the first part of the study, after an overnight fast, a tracer dose of [U-13C]glucose was infused at a constant rate along with an infusion of saline for 7 h. In the second part the saline infusion was replaced by glucose at 4.25 mg min-1 kg-1. In both studies 15 mmol of sodium acetate was given by mouth at 15 min intervals from the fourth to the sixth hour. Glucose turnover, respiratory quotient, metabolic rate and blood levels of acetate, 3-hydroxybutyrate, lactate, insulin, glucagon and gastric inhibitory polypeptide were measured. 3. Glucose turnover rates (means +/- SEM) were 1.88 +/- 0.1 mg min-1 kg-1 during fasting and 4.0 +/- 0.08 mg min-1 kg-1 during glucose infusion. Acetate had no effect on glucose turnover, insulin, glucagon and gastric inhibitory polypeptide levels, but temporarily halted the rise in free fatty acids seen during the fasting study. No changes in oxygen consumption or carbon dioxide output occurred, in keeping with previous observations that acetate substitutes for lipid oxidation during metabolism and has no direct effect on glucose turnover.

3-Hydroxybutyric Acid↗
PubMed1988

Protein metabolism during treatment of chest infection in patients with cystic fibrosis.

Six cystic fibrosis patients with pulmonary exacerbations were studied to determine the effect of antibiotic treatment on protein nutritional status. Indirect calorimetry, nitrogen balance, protein turnover, urinary 3-methylhistidine, plasma albumin, prealbumin transferrin, and cortisol were measured before and after treatment. N loss averaged 16 and 17% on each balance. N in the sputum was up to 4.5% of absorbed N intake. At the peak of infection, protein synthesis, degradation, and urinary 3-methylhistidine were significantly higher than during recovery (31%, 28%, and 60%, respectively). On recovery a significant fall in blood sugar, albumin, morning cortisol and sputum N and a rise in prealbumin was found. Basal metabolic rate and N balance did not change. For patients in the fed state, active infection is associated with higher rates of protein synthesis and degradation. Antimicrobial treatment alters protein dynamics but does not alter measured N balance or the difference between measured protein synthesis and breakdown.

Adolescent↗
PubMed1988

Relationships between plasma isotope enrichments of leucine and alpha-ketoisocaproic acid during continuous infusion of labelled leucine.

The ratio at steady-state of alpha-ketoisocaproic acid (KIC) to leucine 13C enrichments in plasma during continuous infusion of [13C]leucine was examined in 58 studies under a variety of conditions. The ratio was lower (P less than 0.001) in 'arterialized' venous plasma (mean +/- SD 0.85 +/- 0.09) than in deep venous plasma (0.95 +/- 0.08), the sampling site enrichment differences being greater for leucine than for KIC. Variation in the ratio between the various conditions studied was largely explained by analytical variation. Three normal subjects were given an intravenous bolus dose of L-[1-13C, 15N]leucine. Both [13C]KIC and [13C]leucine appeared quantitatively in plasma within 10 min, indicating that both transamination of leucine and KIC, and their equilibration between intracellular fluid and plasma, is rapid. This study suggests that changes in sampling site, rather than in study conditions, are more likely to lead to variation in the KIC:leucine enrichment ratio. The lesser variation for KIC, and the rapid equilibration of the [13C]leucine bolus, favour KIC as tracee for [13C]leucine protein turnover studies.

Adult↗
PubMed1988

Leucine incorporation into mixed skeletal muscle protein in humans.

Fractional mixed skeletal muscle protein synthesis (FMPS) was estimated in 10 postabsorptive healthy men by determining the increment in the abundance of [13C]-leucine in quadriceps muscle protein during an intravenous infusion of L-[1-13C]leucine. FMPS in our subjects was 0.046 +/- 0.003%/h. Whole-body muscle protein synthesis (MPS) was calculated based on the estimation of muscle mass from creatinine excretion and compared with whole-body protein synthesis (WBPS) calculated from the nonoxidative portion of leucine flux. A significant correlation (r2 = 0.73, P less than 0.05) was found between MPS (44.7 +/- 3.4 mg.kg-1.h-1) and WBPS (167.8 +/- 8.5 mg.kg-1.h-1). The contribution of MPS to WBPS was 27 +/- 1%, which is comparable to the reports in other species. Morphometric analyses of adjacent muscle samples in eight subjects demonstrated that the biopsy specimens consisted of 86.5 +/- 2% muscular as opposed to other tissues. Because fiber type composition varies between biopsies, we examined the relationship between proportions of each fiber type and FMPS. Variation in the composition of biopsies and in fiber-type proportion did not affect the estimation of muscle protein synthesis rate. We conclude that stable isotope techniques using serial needle biopsies permit the direct measurement of FMPS in humans and that this estimation is correlated with an indirect estimation of WBPS.

Adult↗
PubMed1988

Effect of beta-hydroxybutyrate on whole-body leucine kinetics and fractional mixed skeletal muscle protein synthesis in humans.

Because intravenous infusion of beta-hydroxybutyrate (beta-OHB) has been reported to decrease urinary nitrogen excretion, we investigated in vivo metabolism of leucine, an essential amino acid, using L-[1-13C]leucine as a tracer during beta-OHB infusion. Leucine flux during beta-OHB infusion did not differ from leucine flux during normal saline infusion in nine normal subjects, whereas leucine oxidation decreased 18-41% (mean = 30%) from 18.1 +/- 1.1 mumol.kg-1.h-1 (P less than 0.01), and incorporation of leucine into skeletal muscle protein increased 5-17% (mean = 10%) from 0.048 + 0.003%/h (P less than 0.02). Since blood pH during beta-OHB infusion was higher than the pH during saline infusion, we performed separate experiments to study the effect of increased blood pH on leucine kinetics by infusing sodium bicarbonate intravenously. Blood pH during sodium bicarbonate infusion was similar to that observed during the beta-OHB infusion, but bicarbonate infusion had no effect on leucine flux or leucine oxidation. We conclude that beta-OHB decreases leucine oxidation and promotes protein synthesis in human beings.

3-Hydroxybutyric Acid↗
PubMed1988

Reproducibility of whole-body protein turnover measurements in an 'ideal' metabolic subject.

Whole-body protein turnover measurements using the single dose 15N-glycine technique have been made in a patient completely paralysed by the Guillaine-Barré syndrome. Variation (difference x 100/mean) between the results of the studies was better than 0.75 per cent for protein flux, better than 0.85 per cent for protein breakdown, and better than 5 per cent for protein synthesis.

Dietary Proteins↗
PubMed1987

Effect of intravenous insulin treatment on in vivo whole body leucine kinetics and oxygen consumption in insulin-deprived type I diabetic patients.

In vivo leucine metabolism was studied after an overnight fast in nine type I diabetic patients and nine healthy control subjects using L-[1-13C] leucine as a tracer. In the insulin-deprived state, leucine flux (reflecting proteolysis), leucine oxidation, and plasma leucine concentrations were higher in the diabetic patients than in the control subjects (P less than .001). In 4 of the 9 insulin-deprived diabetic patients, a four-hour intravenous insulin treatment decreased plasma glucose and leucine concentrations and leucine flux, but failed to decrease leucine oxidation. In the remaining 5 of the 9 diabetic patients, uninterrupted insulin treatment prior to the study and a seven-hour intravenous insulin treatment during the study period decreased not only the concentrations of plasma glucose and leucine and leucine flux, but also leucine oxidation (P less than .01). In all 9 diabetic patients the nonoxidative portion of leucine flux (reflecting protein synthesis) decreased during insulin treatment (P less than .01), but this decrease was lower than that of leucine flux (reflecting proteolysis), and therefore protein was conserved during insulin treatment. We conclude that the effect of insulin on proteolysis (reflected by leucine flux) is more rapid than its effect on leucine oxidation, but on aggressive insulin treatment accelerated leucine oxidation also was decreased in type I diabetic patients.

Adult↗
PubMed1987

Decrease in human quadriceps muscle protein turnover consequent upon leg immobilization.

Quadriceps muscle protein turnover was assessed in the post-absorptive state in six men immediately after the end of unilateral leg immobilization (37 +/- 4 days) in a plaster cast after tibial fracture. A primed-constant intravenous infusion of L-[1-13C]leucine was administered over 7 h. Quadriceps needle biopsies, taken bilaterally at the end of the infusion, were analysed for muscle protein leucine enrichment with 13C. Quadriceps muscle protein synthetic rate, calculated from the fractional incorporation of [13C]leucine into protein compared with the average enrichment of blood alpha-ketoisocaproate, was 0.046 +/- 0.012%/h in the uninjured leg, but was only 0.034 +/- 0.007%/h in the quadriceps of the previously fractured leg (P less than 0.05, means +/- SD). Muscle RNA activity (i.e. protein synthetic rate per RNA) fell from 0.27 +/- 0.08 microgram of protein synthesized h-1 microgram-1 of RNA in the control leg to 0.14 +/- 0.03 microgram of protein synthesized h-1 microgram-1 of RNA in the immobilized leg (P less than 0.02). Immobilization was associated with a significant atrophy of type I muscle fibres (mean diameter 69.5 +/- 21 microns immobilized, 81.1 +/- 18 microns control, P less than 0.05), but no significant change occurred in type II fibre diameter. Mean quadriceps fibre volume calculated from the values for fibre diameter and percentage of each fibre type, was smaller in the injured leg by 10.6%; this value was near to the calculated difference in muscle thigh volume (calculated from thigh circumference and skin-fold thickness) which was less by 8.3%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Influence of fasting on leucine and muscle protein metabolism across the human forearm determined using L-[1-13C,15N]leucine as the tracer.

1. We have used L-[1-13C,15N]leucine as the substrate tracer to study leucine and muscle protein metabolism across the forearm of eight normal fasting adults. 2. The rates of protein synthesis and breakdown, de- and re-amination of leucine, and the oxidative decarboxylation of its keto acid were calculated directly from the arteriovenous metabolite balances and isotope dilutions as described by the metabolic model. 3. The results were compared with those obtained previously when subjects were fed. The effects of fasting on protein and leucine metabolism were a significant decrease in protein synthesis from 127 (SEM 11; n = 6) to 70 (SEM 6; n = 12) nmol of leucine min-1 100 ml-1 of forearm tissue (P less than 0.001) and a marked decrease in leucine catabolism in the forearm muscle. 4. This model has demonstrated that each subject was in negative protein balance across the forearm during fasting while positive during feeding, the mean values being -29(SEM 5; n = 12) and +39(SEM 9; n = 6) nmol of leucine min-1 100 ml-1 of forearm tissue respectively. 5. These results are sufficiently encouraging to suggest a role for this model in future studies on muscle protein metabolism.

Adult↗
PubMed1987

Protein and energy metabolism with biosynthetic human growth hormone after gastrointestinal surgery.

The effect of biosynthetic human growth hormone (BSHGH) on postoperative protein and energy metabolism has been studied in patients who had major gastrointestinal surgery. Seven patients received placebo and seven patients received BSHGH, 0.1 mg/kg/24 h, for the first six postoperative days. Mean total nitrogen excretion was significantly lower with BSHGH (31.5 +/- 2.4 g N) (2287 +/- 160 mmol) than with placebo (42.7 +/- 3.1 g N) (3049 +/- 219 mmol) over the 6-day study period. The mean daily measured energy expenditure over days 3-6 was higher with BSHGH (31.3 +/- 1.8 kcal/kg LBM/24 h) (131 +/- 7 kJ/kg LBM/24 h) than with placebo (27.6 +/- 0.8 kcal/kg LBM/24 h) (114 +/- 2 kJ/kg LBM/24 h). Fat oxidation with BSHGH (2.05 +/- 0.26 mg/kg LBM/24 h) was greater than with placebo (1.5 +/- 0.17 mg/kg LBM/24 h) and protein oxidation was less with BSHGH (0.68 +/- 0.07 g/kg LBM/24 h) than with placebo (0.9 +/- 0.09 g/kg LBM/24 h) on days 1-6. Postoperative nitrogen turnover (BSHGH 943 +/- 174 mg N/kg LBM/24 h, placebo 557 +/- 50 mg N/kg LBM/24 h) (BSHGH 67 +/- 13 mmol/kg LBM/24 h, placebo 40 +/- 4 mmol/kg LBM/24 h), protein synthesis (BSHGH 5.31 +/- 1.09 g prot/kg LBM/24 h, placebo 2.54 +/- 0.33 g prot/kg LBM/24 h) and protein breakdown (BSHGH 5.90 +/- 1.09 g prot/kg LBM/24 h, placebo 3.48 +/- 0.31 g prot/kg LBM/24 h) were greater with BSHGH. On the first postoperative day serum insulin and blood glucose levels were higher with BSHGH than with placebo, and on days 4 and 7 serum somatomedin-C levels were significantly elevated. This study shows that BSHGH alters postoperative protein and energy metabolism by reducing protein oxidation and increasing fat oxidation with raised rates of whole body nitrogen turnover.

Adult↗
PubMed1987

Effect of diazoxide or glucagon on hepatic glucose production rate during extreme neonatal hypoglycaemia.

The relation between hepatic glucose production rate (HGPR) and plasma concentrations of insulin and glucagon was investigated in four term neonates who had severe hypoglycaemia. The hepatic glucose production rate was less than 20% of normal for fasting term neonates in all four babies and yet insulin concentrations were never greater than 12 microU/ml; two babies had very low glucagon concentrations (less than 60 ng/l). Two further neonates with similar histories also had plasma glucagon concentrations that were also extremely low (less than 20 ng/l). A single intravenous bolus of glucagon caused a rapid rise in hepatic glucose production rate towards the normal range, which was sustained for many hours after the bolus had been given. Diazoxide given to one baby suppressed previously 'normal' insulin concentrations still further (4.2 to less than 1.6 microU/ml) and thereby restored the hepatic glucose production rate to normal. In view of the normal plasma insulin concentrations at a time when the hepatic glucose production rate was reduced, we feel that the absolute concentration of insulin may be less important than the insulin/glucagon molar ratio in the control of glucose homeostasis in this group of infants. The changing of this ratio by means of boluses of glucagon may be useful in preventing rebound hypoglycaemia, which so often occurs when dextrose infusions are reduced either accidentally or in an attempt to restart oral feeds.

Blood Glucose↗