Regulation of protein metabolism in middle-aged, premenopausal women: roles of adiposity and estradiol

The age-related loss of fat-free mass (FFM) is accelerated in women during the middle-age years and continues at an increased rate throughout the postmenopausal period. Because protein is the primary structural component of fat-free tissue, changes in FFM are largely due to alterations in protein metabolism. Knowledge of the hormonal and physiological correlates of protein metabolism in middle-aged women, therefore, has important implications for understanding the mechanisms underlying changes in FFM. We measured leucine kinetics (expressed relative to FFM: micromol/kg FFM/h) in 46 middle-aged, premenopausal women (mean +/- SD, 47 +/- 3 yr) after an overnight fast (i.e. basal) and during euglycemic hyperinsulinemia (40 mU/m2/min) using a 5.5-h infusion of [1-13C]leucine. Additionally, we measured insulin-stimulated glucose disposal by euglycemic hyperinsulinemic clamp, body composition by dual energy x-ray absorptiometry, abdominal fat distribution by computed tomography, and hormone levels by RIA as possible correlates of protein metabolism. Under basal conditions, stepwise regression analysis showed that leucine appearance (i.e. protein breakdown) was related to percent body fat and serum estradiol (r2 = 40%; P < 0.01), and leucine oxidation was related to serum estradiol and percent body fat (r2 = 26%; P < 0.05). Under euglycemic hyperinsulinemic conditions, no variables correlated with the percent change in leucine appearance. The percent change in leucine oxidation was related to intraabdominal adipose tissue area and glucose disposal rate (r2 = 48%; P < 0.01). Correlates and r2 values for nonoxidative leucine disposal (i.e. protein synthesis) under basal and euglycemic hyperinsulinemic conditions were similar to those observed for leucine appearance. From these results, we conclude that adiposity and/or serum estradiol may contribute to the regulation of protein metabolism and FFM in middle-aged, premenopausal women.     

Effects of growth hormone and/or sex steroid administration on whole-body protein turnover in healthy aged women and men

Aging is associated with reduced activities of the growth hormone (GH), insulin-like growth factor I (IGF-I), and sex steroid axes, and with decreased lean body mass and protein synthesis. Using a randomized, double-blinded, placebo-controlled design, we studied the effects of 6 months of administration of GH alone, sex hormone alone (hormone replacement therapy in women, testosterone enanthate [T] in men), or GH plus sex hormone on protein turnover in healthy men (n=60) and women (n=43), aged 65 to 88 years (mean, 71+/-4.4 years). Growth hormone administration significantly increased IGF-I levels in both sexes, more markedly in men. Sex steroid administration increased the levels of estrogen and testosterone in women and men, respectively (P=.05). Protein turnover was measured before and after the 26-week treatment period by means of a primed, constant l-[1-(13)C]leucine infusion. In men, GH plus T administration increased leucine flux from 80.2+/-2.8 to 93.6+/-4.2 micromol.h-1.kg-1 (P=.02). Leucine oxidation did not change significantly after hormone treatment in either sex. Growth hormone treatment led to nonsignificant upward trends in nonoxidative leucine disposal in men (9.1+/-5.2 mol.h-1.kg-1) and women (7.6+/-7.1 mol.h-1.kg-1). Among all groups combined, changes in nonoxidative leucine disposal were directly related to those of serum IGF-I level (r=0.248, P<.02). Whole-body protein turnover increased in GH plus T-treated men (0.6+/-0.2 g protein.kg-1.d-1; P<.01). These data suggest that low-dose GH administration increases protein synthesis in healthy aged women and men, and that the coadministration of testosterone plus GH enhances this effect in elderly men.     

The influence of sex on the protein anabolic response to insulin

We hypothesize that sex influences whole-body protein anabolism in the postabsorptive state and in response to hyperinsulinemia. Kinetics of 3-(3)H-glucose and (13)C-leucine were studied in 16 men and 15 women after energy- and protein-controlled diets, before and during a hyperinsulinemic, euglycemic, isoaminoacidemic clamp. In the postabsorptive state, women had 20% higher rates of leucine Ra (protein breakdown) and nonoxidative Rd (synthesis) adjusted for fat-free mass than men but net leucine balance was as negative. In response to hyperinsulinemia, leucine oxidation rates increased only in women and the change in net leucine balance was less than in men. Net leucine balance during the clamp correlated with rates of glucose disposal. Thus, women showed greater protein turnover rates when adjusted for fat free mass in the postabsorptive state, and lesser insulin sensitivity of protein anabolism and net protein accretion. A relationship exists between the protein anabolic response to insulin and the insulin sensitivity of glucose metabolism.     

The effects of growth hormone and/or testosterone on whole body protein kinetics and skeletal muscle gene expression in healthy elderly men: a randomized controlled trial

CONTEXT: Alterations of protein turnover may contribute to the progressive decline of muscle mass with aging. OBJECTIVE: Our objective was to examine the effects of near-physiological recombinant human GH and/or testosterone (T) administration to older men on whole body protein kinetics and muscle gene expression. DESIGN, SETTINGS, AND PARTICIPANTS: A 6-month randomized, double-blind, placebo-controlled trial in 21 healthy elderly men aged 65-75 yr, was performed. Participants were randomized to receive placebo GH and placebo T, rhGH and placebo T (GH), T and placebo GH (T), or rhGH and T (GHT). INTERVENTIONS: The leucine rate of appearance (index of proteolysis), nonoxidative leucine disposal rate (an index of protein synthesis), and leucine oxidation rate were measured with an infusion of l-[1-(13)C] leucine. Muscle biopsies for the measurement of gene expression were performed. Body composition and aerobic capacity (maximal oxygen capacity) were measured. RESULTS: Serum IGF-I levels increased significantly with GH and GHT (P < 0.001) compared with placebo. T increased significantly only in the T group (P = 0.028). Leucine rate of appearance and nonoxidative leucine disposal rate increased with GH (P = 0.015, P = 0.019) and GHT (P = 0.017, P = 0.02), but leucine oxidation did not change significantly in any treatment group. Midthigh muscle mass and maximal oxygen capacity increased (P < 0.04) with GHT only. Expression of muscle function genes did not change significantly, but the within-group comparisons revealed a significant increase of androgen receptor expression in the GHT group (P = 0.001). CONCLUSION: This study showed that 6-month treatment with low-dose GH alone or with T in healthy elderly men produces comparable increments in whole body protein turnover and protein synthesis.     

p38 Mitogen-activated Protein Kinase is Not Activated in the Quadriceps of Patients with Stable Chronic Obstructive Pulmonary Disease

Abstract

Quadriceps weakness is associated with a poor prognosis in COPD. Several data suggest that immobility and muscle wasting may be related through up-regulation of the p38 Mitogen associated protein kinase (MAPK) signalling pathway. We therefore hypothesised that this might occur in the quadriceps of COPD patients. We studied 105 stable COPD outpatients (mean FEV₁ 43.9% predicted) and 27 age and gender matched controls. We measured fat-free mass, quadriceps strength and daily physical activity using triaxial accelerometry. A quadriceps biopsy was obtained in which components of the p38-MAPK signalling pathway were examined. Patients had reduced fat-free mass index (16.1 (2.2) kg/m² vs 17.2 (2.2) kg/m², p = 0.02) and exhibited quadriceps weakness (mean (SD) maximal voluntary contraction force 72.1% (18.7) predicted and 82.3% (7.1) predicted for patients and controls respectively, p = 0.01). Physical activity was significantly reduced in the patient group; in particular mean (SD) locomotion time was 101 () minutes/12 hours in controls and 48 () minutes in patients (p < 0.0001). However, in biopsies obtained from these patients, no differences were observed for total or phosphorylated HSP27 or p38 MAPK protein or p38 MAPK mRNA (MAPK14); of the downstream products both GADD45β and c-jun mRNA were reduced in COPD patients while c-myc was not different from controls. No parameter correlated with physiological data within the patient group. We conclude that, despite the presence of reduced fat-free mass, quadriceps weakness and inactivity, p38 MAPK signalling was not up-regulated in skeletal muscle of stable out-patients with COPD.     

Whole-body protein metabolism assessed by leucine and glutamine kinetics in adult patients with active celiac disease

To assess the effect of increased renewal of intestinal epithelial cells on leucine and glutamine (Gln) turnover, 4-hour intravenous infusions of l-[1-¹³C]leucine and l-[2-¹⁵N]Gln were administered to five adult patients with active celiac disease in the postabsorptive state. There was a 35% increase in leucine flux (micromoles per kilogram per hour) in patients (117 ± 17) compared with healthy controls (96 ± 11, P < .03). Gln flux was increased by 13% in patients (377 ± 35) versus controls (335 ± 16, P < .04). These results suggest that active celiac disease, characterized by villous atrophy and crypt cell hyperplasia, is associated with a dramatic increase in whole-body protein breakdown as assessed by ¹³C-leucine, which may contribute per se to the protein malnutrition status of the patients. The increase in Gln utilization as assessed by l-[2-¹⁵N]Gln was moderate, but may have been offset due to the villose atrophy and ensuing reduced intestinal epithelial cell mass. The results are consistent with the concept that increased renewal of intestinal epithelial cells represents a sizable fraction of whole-body protein turnover and that Gln is an important fuel for epithelial intestinal cells in vivo.     

The effects of growth hormone on protein metabolism in adult growth hormone deficient patients

OBJECTIVE Growth hormone treatment given to adult growth hormone deficient patients leads to an increase in lean body mass by an unknown mechanism. The aim of this study was to investigate the actions of growth hormone treatment on protein metabolism in adult growth hormone deficient patients. DESIGN Double-blind, placebo controlled trial of recombinant human growth hormone (0 018 U/kg/day for 1 month followed by 0.036 U/kg/day for 1 month) with isotopic whole body protein turnover studies at 0 and 2 months. PATIENTS Eighteen adult growth hormone deficient patients (nine male, nine female of mean age 46.6 (range 30–56). MEASUREMENTS Whole body isotopic leucine turnover using L-1-¹³C-leucine measuring leucine R a (a measure of protein degradation), non-oxidative leucine R d (a measure of protein synthesis) and leucine oxidation rate. RESULTS Lean body mass (P<0.02), circulating insulinlike growth factor I (P<0 01) and insulin (P<0.02) were significantly increased at 2 months in the treatment group but there was no change in the placebo group. When expressed in relation to body weight, leucine fia and non-oxidative leucine fid increased (P<0.01) and leucine oxidation decreased (P<0.02) after 2 months growth hormone treatment. When expressed in relation to lean body mass non-oxidative leucine R d increased (P<0.02) and leucine oxidation decreased (P<0.02) but there was no significant change in leucine R a after 2 months growth hormone treatment. In the placebo group there were no significant changes in leucine metabolism expressed as lean body mass or body weight after 2 months. changes in leucine metabolism expressed as lean body mass or body weight after 2 months. CONCLUSION These results indicate that the increase in lean body mass resulting from growth hormone treatment in adult growth hormone deficient patients is due to an increase in protein synthesis.     

Protein metabolism in acromegaly: differential effects of short- and long-term treatment

CONTEXT: GH acutely increases body protein by stimulating protein synthesis and reducing protein oxidation. OBJECTIVE: The objective of the study was to determine whether these changes in protein metabolism are sustained in long-term GH excess and reversed by correction. DESIGN: We conducted a cross-sectional study in 16 acromegalic and 18 normal subjects and a longitudinal study in which acromegalic subjects were studied before and after short-term (n=8) or long-term (n=10) treatment. SETTING: The study was conducted at a clinical research center. MAIN OUTCOME MEASURES: Whole-body rates of leucine appearance (leucine Ra; an index of protein breakdown), leucine oxidation, and nonoxidative leucine disposal (NOLD; an index of protein synthesis) estimated using infusion of 1-[13C] leucine were measured. RESULTS: Leucine Ra and NOLD were greater (P<0.01) in acromegalic compared with normal subjects, whereas leucine oxidation did not differ. Leucine oxidation increased significantly (P<0.05) after short-term treatment but returned to baseline after long-term treatment. Both leucine Ra and NOLD decreased significantly (P<0.05) after short- and long-term treatment. Adjustment for body composition did not affect results. CONCLUSIONS: In acromegalic subjects, protein breakdown and synthesis are increased, whereas protein oxidation does not differ from normal subjects. Protein oxidation increases transiently, whereas protein breakdown and synthesis are stably reduced after treatment. Because protein oxidation represents irreversible loss, we conclude that the normal state of protein oxidation found in acromegaly and after long-term treatment represents metabolic adaptation, which maintains protein mass at a steady state after stable changes in GH status.     

Effects of reduced energy intake on protein utilization in obese children

Dietary treatment of pediatric obesity is a challenge given the need for adequate nutrients to support the maintenance of lean tissue and growth. The primary purpose of this investigation was to assess the effects of reduced energy intake on protein turnover in obese children aged 8 to 10 years. Following a 2-week baseline period, 16 subjects reduced energy intake during a 6-week intervention period. At baseline and following the intervention, ¹⁵N-glycine methodology was used to measure nitrogen flux (Q), protein synthesis (PS), protein breakdown (PB), and net turnover ([NET] PS — PB). Other criterion measures included resting metabolic rate (RMR), fat mass (FM), fat-free mass (FFM), urinary creatinine to height ratio (Cr:Ht), and nitrogen balance (NB). On average, subjects lost 2.2 ± 0.3 kg, of which greater than 85% was FM. Decreased Q (P = .03) indicated downregulation of protein turnover in response to diet-induced weight loss. While PB did not change, NET declined slightly (P = .06) as a consequence of reduced PS (P = .03). Reductions in FFM (P = .09), Cr:Ht (P = .02), and NB (P = .03) accompanied alterations in protein turnover, but there was no change in the RMR. In conclusion, while short-term therapy promoted the loss of FM and did not compromise RMR, practitioners must be cautious when prescribing diets, given the observed changes in protein utilization and somatic protein status. Longitudinal studies are needed to further characterize the metabolic responses of obese children to long-term diet therapy.     

Decreased respiratory quotient in relation to resting energy expenditure in HIV-infected and noninfected subjects

The purpose of this study was to evaluate the relationship of respiratory quotient (RQ), a surrogate marker of substrate oxidation, as well as body composition and dietary intake to resting energy expenditure (REE) among HIV-infected patients in the current era of highly active antiretroviral therapy and among non-HIV-infected control subjects. Resting energy expenditure is increased in HIV-infected patients; but little is known regarding the potential contribution of altered substrate metabolism, body composition, and dietary intake to increased energy expenditure in this population. Respiratory quotient, REE, body composition, and dietary intake parameters were assessed in 283 HIV-infected patients and 146 community-derived HIV-negative controls who were evaluated for metabolic studies between 1998 and 2005. Respiratory quotient was lower (0.83 ± 0.00 vs 0.85 ± 0.01, P = .005), whereas REE adjusted for fat-free mass (FFM) was higher (31.8 ± 0.3 vs 29.8 ± 0.3 kcal/[d kg], P ≤ .0001), in HIV-infected compared with control subjects. In multivariate modeling among HIV-infected patients, including age, sex, and parameters of immune function, FFM (β = 24.811334, P < .0001), visceral adiposity (β = .7182746, P = .008), and total body fat (β = 8.0506839, P = .041) were positively associated with REE, whereas RQ was negatively associated with REE (β = −528.4808, P = .024). Overall r² was equal to 0.705 and P was less than .0001 for the model. In control subjects, by contrast, only visceral adiposity (β = 1.0612073, P = .004), total body fat (β = 15.805547, P = .010), and FFM (β = 22.613005, P < .0001) were significant predictors of REE; and there was no relationship with RQ. Overall r² was equal to 0.825 and P was less than .0001 for the model. These data suggest that alterations in substrate metabolism may contribute to increased REE in HIV-infected patients compared with control subjects.     

Increased postabsorptive and exercise-induced whole-body glucose production in patients with chronic obstructive pulmonary disease

Skeletal muscle biopsy studies have consistently shown a decreased oxidative phenotype in patients with moderate to severe chronic obstructive pulmonary disease (COPD). Limited information is available regarding potential adaptations or abnormalities in anaerobic metabolism and glucose homeostasis. Whole-body glucose production was assessed at rest and during exercise in COPD patients with moderate disease severity (forced expiratory volume in 1 second, 52% ± 3%), prestratified into normal-weight (n = 7; body mass index [BMI], 27.5 ± 0.9 kg·m⁻²) and underweight subjects (n = 6; BMI, 20.6 ± 0.7 kg·m⁻²), and in 8 healthy controls matched for age and BMI with the normal-weight COPD group. Glucose tolerance was normal in all subjects. Rate of appearance (R_a) of glucose at rest and during submaximal cycling exercise was measured in postabsorptive state by infusion of stable isotope tracer [6,6-²H₂]glucose. Resting glucose R_a was significantly enhanced in underweight COPD patients compared with controls (16.7 ± 0.3 vs 15.1 ± 0.4 μmol·kg fat-free mass⁻¹·min⁻¹, P < .05) and was inversely related to fat-free mass (r = −0.75, P < .01). Furthermore, the exercise-induced increase in glucose R_a was enhanced in COPD patients (81.9% ± 3.4% vs 72.1% ± 2.0%, P = .05), resulting in elevated end-of-exercise glucose output. Differences were most pronounced in underweight patients, who were also characterized by enhanced plasma catecholamine levels and decreased insulin concentrations (all, P < .05). In normal-weight patients, there was evidence for decreased insulin sensitivity assessed by homeostatic modeling technique. Whole-body glucose production is increased in underweight COPD patients with normal glucose tolerance. It is hypothesized that lowered body weight in COPD has unique effects on glucose uptake despite reduced skeletal muscle oxidative capacity, relative hypoxemia, and sympathetic activation.     

Growth hormone blunts protein oxidation and promotes protein turnover to a similar extent in abdominally obese and normal-weight women

Abdominally obese individuals have reduced 24-h plasma GH concentrations. Their normal plasma IGF-I levels may reflect GH hypersensitivity. Alternatively, obesity-associated hyposomatotropism may cause less biological effect in target tissues. We therefore determined whole-body responsiveness to the anabolic effects of GH in abdominally obese (OB) and normal weight (NW) premenopausal women. A 1-h iv infusion of GH or placebo was randomly administered to six NW (body mass index, 21.1 +/- 1.9 kg/m(2)) and six OB (body mass index, 35.5 +/- 1.5 kg/m(2)) women in a cross-over design. Endogenous insulin, glucagon and GH secretion was suppressed by infusion of somatostatin. Whole-body protein turnover was measured using a 10-h infusion of [(13)C]-leucine. GH administration induced a similar plasma GH peak in NW and OB women (49.8 +/- 10.4 vs. 45.1 +/- 5.6 mU/liter). GH, compared with placebo infusion, increased nonoxidative leucine disposal, P < 0.0001) and endogenous leucine appearance (R(a), P = 0.0004) but decreased leucine oxidation (P = 0.0051). All changes were similar in both groups. Accordingly, whole-body GH responsiveness, defined as the maximum response of nonoxidative leucine disposal, leucine R(a), and oxidation per unit of GH, was not different in OB and NW women (0.25 +/- 0.18 vs. 0.19 +/- 0.17 micro mol/kg.h, 0.21 +/- 0.23 vs. 0.13 +/- 0.17 micro mol/kg.h, and -0.10 +/- 0.08 vs. -0.08 +/- 0.05 micro mol/kg.h, respectively). These results indicated that whole-body tissue responsiveness to the net anabolic effect of GH is similar in OB and NW women. Hence, we inferred that hyposomatotropism may promote amino acid oxidation and blunt protein turnover in abdominal obesity. However, hyposomatotropism cannot account for all anomalous features of protein metabolism in abdominally obese humans.     

High dose growth hormone exerts an anabolic effect at rest and during exercise in endurance-trained athletes

The anabolic actions of GH in GH-deficient adults and children are well documented. Replacement with GH in such individuals promotes protein synthesis and reduces irreversible loss of protein through oxidation. Although GH is known to be self-administered by athletes, its protein metabolic effects in this context are unknown. This study was designed to determine whether 4 wk of high dose recombinant human GH (r-hGH) administration altered whole body leucine kinetics in endurance-trained athletes at rest and during and after 30 min of exercise at 60% of maximal oxygen uptake. Eleven endurance-trained male athletes were studied, six randomized to receive r-hGH (0.067 mg/kg.d), and five to receive placebo. Whole body leucine turnover was measured at rest and during and after exercise, using a 5-h primed constant infusion of 1-[(13)C]leucine, from which rates of leucine appearance (an index of protein breakdown), leucine oxidation, and nonoxidative leucine disposal (an index of protein synthesis) were estimated. Under resting conditions, r-hGH administration increased rate of leucine appearance and nonoxidative leucine disposal, and reduced leucine oxidation (P < 0.01). This effect was apparent after 1 wk, and was accentuated after 4 wk, of r-hGH administration (P < 0.05). During and after exercise, GH attenuated the exercise-induced increase in leucine oxidation (P < 0.05). There were no changes observed in placebo-treated subjects compared with the baseline study. We conclude that GH administration to endurance-trained male athletes has a net anabolic effect on whole body protein metabolism at rest and during and after exercise.     

Resting energy expenditure and nutritional status in children with juvenile rheumatoid arthritis.

OBJECTIVE: Undernutrition is frequently encountered in children with juvenile rheumatoid arthritis (JRA). We assessed resting energy expenditure (REE) in relation to nutritional status and body composition in patients with JRA. METHODS: We selected 33 children (age 6 to 18 yrs) with JRA (13 oligoarticular, 10 polyarticular, 10 systemic JRA) and 17 controls matched for age and sex. Nutritional status was assessed for height, weight, and fat-free mass (FFM), and REE was measured with indirect calorimetry. RESULTS: Nutritional status in the patients with systemic JRA was diminished compared to the controls for height (140 vs. 159 cm; p<0.01) and FFM (28 vs. 38 kg; p = 0.03). Oligo and polyarticular patients with JRA had normal height and FFM. No significant differences existed in crude REE among the groups. However, after correcting REE for body weight and FFM, the patients with systemic JRA, compared to controls, had 18% higher REE per kg body weight (159 vs. 134 kJ/kg/day; p<0.01) and 21% higher REE per kg FFM (196 vs. 162 kJ/kg/day; p<0.01). Oligo and polyarticular JRA patients had 8% increased values for REE per kg body weight or FFM, but these differences were not statistically significant. CONCLUSION: Patients with systemic JRA show stunting, low FFM, and a significantly increased REE when nutritional status is taken into account. These data suggest that assessment of individual energy requirements should include correction for fat-free mass in the treatment of malnutrition in patients with systemic JRA.     

Impact of regional and total body composition and hormones on resting energy expenditure in overweight postmenopausal women

The independent impact of regional and total body composition and sex and thyroid hormone levels on resting energy expenditure (REE) was assessed in 121 healthy, overweight (body mass index [BMI], 25 to 42 kg/m²), postmenopausal women (aged 49 to 58 years). REE was measured by indirect calorimetry with a ventilated hood, and the total, trunk, and peripheral body composition by dual-energy x-ray absorptiometry (DXA). Sex and thyroid hormone levels were also measured. REE correlated significantly (P < .05) better with trunk lean tissue mass ([LTM] r = .61) than with total-body (r = .53) or peripheral LTM (r = .30). Trunk LTM (R² = .37), total-body fat tissue mass ([FTM] R² = .04), androstenedione (R² = .03), and total triiodothyronine ([T₃] R² = .02) were all significantly independently associated with REE. Together they explained 46% (model R²) of the interindividual variation in REE, with a standard error of estimate (SEE) of 549 kJ/d. We conclude that the interindividual variation in REE is explained mainly by differences in the visceral component of LTM, with additional minor information from the total-body FTM, androstenedione, and T₃.     

Effect of insulin and plasma amino acid concentration on leucine metabolism in cirrhosis

Clinically stable patients with cirrhosis demonstrate insulin resistance with regard to glucose metabolism. However, much less is known about the two major factors, insulin and plasma amino acid concentration, that regulate protein metabolism in cirrhotic patients. To examine this question, we performed paired euglycemic insulin clamp studies in combination with 14C-leucine and indirect calorimetry. In the first study insulin alone was infused, and the plasma amino acid concentration was allowed to decline. During the second study a balanced amino acid solution was infused with insulin to increase the total plasma amino acid concentration approximately twofold. Insulin-mediated glucose disposal (4.68 vs. 6.45 mg/kg-min, p less than 0.01) was significantly impaired by 30% in cirrhotic patients during both insulin clamp studies. In the postabsorptive state, cirrhotic patients manifested low plasma leucine (76 vs. 102 mumol/L) and alpha-ketoisocaproate (19 vs. 30 mumol/L) concentrations, but all parameters of leucine turnover were normal. When insulin alone was infused, the endogenous leucine flux (an index of protein degradation) declined similarly in cirrhotic patients (30.8 mumol/m2-min) and control (26.9) subjects, and this was accompanied by a similar decrease in plasma leucine concentration (31% vs. 33%). The decline in circulating leucine concentration was accompanied by a parallel decline in leucine oxidation (5.1 vs. 4.6 mumol/m2-min) and nonoxidative (28.9 vs. 26.0 mumol/m2-min) leucine disposal, which were of similar magnitude in cirrhotic patients and control subjects, respectively. In both cirrhotic patients and control subjects, combined hyperinsulinemia/hyperaminoacidemia elicited a similar stimulation of nonoxidative leucine disposal (an index of protein synthesis) and leucine oxidation while causing a greater suppression of endogenous leucine flux than observed with insulin alone. Thus the suppressive effect of insulin on protein degradation and the stimulatory effect of insulin/amino acid infusion on protein synthesis are not impaired in cirrhotic patients, demonstrating a clear-cut dissociation between the effects of insulin on protein and glucose metabolism.     

Resting energy expenditure and body composition in morbidly obese,obese and control subjects

Resting energy expenditure (REE) was investigated by indirect calorimetry in relation to body composition and to different degrees of obesity in order to assess if a defective energy expenditure contributes to extra body fat accumulation. Differences were found between control subjects (group C; BMI 23±0.5 kg/m², REE 5890±218 kJ/day; mean±SEM) and obese subjects (group O; BMI 34.2±0.9 kg/m², REE 7447±360 kJ/day;P<0.0001) and between group C and morbidly obese subjects (group MO; BMI 49.9±1.6 kg/m², REE 8330±360 kJ/day;P<0.0001); REE was not significantly different between groups O and MO. Body composition data were obtained by means of body impedance analysis. Even though group MO had a fat mass higher than group O, body cell mass, the metabolically active body compartment, was similar in groups O and MO, and this fact may have contributed to the similar REE in the two groups. Multiple regression analysis gave the following equation as the best predictor of REE: REE (kJ/day)+1591±49_BW+74_BCM–737 _G (R ²=0.88), where BW is body weight, BCM is body cell mass andG is a dummy variable coding group membership (group C=1; group O=2; group MO=3). Thus the analysis showed a negative impact of obesity on REE beyond body composition variables.     

Is COPD associated with increased mortality and morbidity in hospitalized pneumonia? A systematic review and meta‐analysis

This review aimed to investigate whether chronic obstructive pulmonary disease (COPD) is associated with increased mortality and morbidity in patients hospitalized with community‐acquired pneumonia (CAP). EMBASE, PubMed and Web of Science were searched for cohort studies and case–control studies investigating the impact of COPD on CAP. The primary outcome was all‐cause mortality, and secondary outcomes included length of hospital stay, intensive care unit (ICU) admission and need for mechanical ventilation. Methodological quality was assessed using the Newcastle–Ottawa Scale. The Mantel–Haenszel method and inverse variance method were used to calculate pooled relative risks (RRs) and mean differences (MD), respectively. Eleven studies (nine cohort studies and two case–control studies), involving 257 958 patients, were included. The overall methodological quality was high. COPD was not associated with increased mortality in hospitalized CAP patients (RR, 1.20; 95% confidence interval (CI): 0.92–1.56; P = 0.19; I² = 55%) in cohort studies, and was associated with reduced mortality in case–control studies (RR, 0.82; 95% CI: 0.74–0.90; P < 0.0001; I² = 80%). COPD was not associated with longer hospital stay (MD, 0.11; 95% CI: ?0.42 to 0.64; P = 0.68; I² = 21%), more frequent ICU admission (RR, 0.97; 95% CI: 0.70–1.35; P = 0.87; I² = 65%), and more need for mechanical ventilation (RR 0.91, 95% CI: 0.71–1.16; P = 0.44; I² = 4%).The current available evidence indicates that COPD may not be associated with increased mortality and morbidity in patients hospitalized with CAP. This conclusion should be re‐evaluated by prospective population‐based cohort studies.     

Associations between BODE Index and Systemic Inflammatory Biomarkers in COPD

Background: COPD is a multicomponent disease and systemic inflammation represents one of the possible mechanisms responsible for its systemic manifestations, including skeletal muscle weakness and cachexia. Fat-free mass index (FFMI) that reflects the skeletal muscle mass, has been shown to be associated with both dyspnoea and exercise capacity. We hypothesized that the multidimensional BODE index, that reflects the multicomponent nature of COPD, might be related to biomarkers of systemic inflammation. We further evaluated associations between FFMI and systemic inflammation. Methods: BODE index and FFMI were calculated in 222 stable COPD patients and 132 smokers or ex-smokers with normal lung function. Systemic inflammation was evaluated with the measurement of leptin, adiponectin, CRP, IL-6, and TNF-α in serum samples of COPD patients. Results: In patients with COPD, both BODE index and FFMI presented significant positive and negative associations respectively with leptin levels (R² 0.61 and 0.65, respectively), whereas FFMI presented an additional negative association with the levels of TNF-α (R² 0.38). No significant associations were observed in smokers or ex-smokers with normal lung function. Conclusions: Both BODE index and FFMI, are related to the circulating levels of leptin in patients with COPD, suggesting a possible role for leptin in the systemic component of COPD. The additional association of FFMI with TNF-α may further support a role of systemic inflammation in muscle wasting in COPD.     

Leucine metabolism in patients with Cushing's syndrome before and after successful treatment

OBJECTIVE Results from studies on the effect of glucocor-ticosteroids on protein turnover in both rat and man have been conflicting. The aim of this study was to investigate the primary cause of muscle wasting in patients with Cushing's syndrome. DESIGN Studies of whole body 1-¹⁴C-leucine turnover in patients with Cushing's syndrome before and after successful treatment, and in control subjects. PATIENTS Eleven patients with Cushing's syndrome before and after (n= 5) treatment and 11 control subjects. MEASUREMENTS Whole body 1-¹⁴C-leucine turnover to determine leucine metabolic clearance rate, leucine production rate, leucine oxidation rate and leucine incorporation into protein. RESULTS Plasma leucine concentration (mean ± SEM 100 ± 6 μ mol/l), leucine metabolic clearance rate (9.97 ± 0.11 μ mol/min/kg), leucine turnover (0.98 ± 0.11 μ mol/min/kg) and leucine incorporation into protein (0.71 ± 0.09 μ mol/min/kg) were all significantly reduced in patients with Cushing's syndrome compared with control subjects (122 ± 6 μ mol/l, P < 0.05; 13.61 ± 1.27 μ mol/min/kg, P < 0.05; 1.65 ± 0.12 μ mol/min/kg, P < 0.05; 1.46 ± 0.10 μ mol/min/kg, P < 0.001, respectively). Leucine oxidation rate was similar in the patients with Cushing's syndrome and control subjects. When leucine metabolism was expressed in terms of lean body mass (LBM) in five patients with Cushing's syndrome and 11 control subjects, leucine MCR, leucine turnover and leucine oxidation were not significantly different in the two groups. However, leucine incorporation into protein was significantly reduced (P< 0.001) in the patients with Cushing's syndrome (1.07 ± 0.20 μ mol/min kg LBM) compared with control subjects (1.95 ± 0.11 μ mol/min/kg LBM). CONCLUSION We conclude from these studies that the muscle wasting associated with Cushing's syndrome is primarily due to a reduction in protein synthesis.