Abstract
ObjectiveInflammatory disease is catabolic and associated with insulin resistance, increased energy expenditure, lipolysis and muscle protein loss. The main contributors to these metabolic adaptations are inflammation, malnutrition and immobilisation. Controlled experimental models incorporating these central elements of hospitalisation are lacking. The aim of this study was to validate such a human experimental model.MethodsIn a randomized crossover design, six healthy young men underwent; (i) overnight fast (CTR), or (ii) exposure to systemic lipopolysaccharide (1 ng/kg) combined with 36-hour fast and bed rest (CAT). The difference in insulin sensitivity between CAT and CTR was the main outcome, determined by a hyperinsulinemic euglycemic glucose clamp. Palmitate, glucose, urea, phenylalanine and tyrosine tracers were infused to estimate metabolic shifts during interventions. Indirect calorimetry was used to estimate energy expenditure and substrate oxidation.ResultsInsulin sensitivity was 41% lower in CAT than in CTR (M-value, mg/kg/min): 4.3 ± 0.2 vs 7.3 ± 1.3, p<0.05. The median (min max) palmitate flux (μmol/min) was higher during CAT than in CTR (257.0 (161.7 365.4) vs 131.6 (92.3 189.4), p = 0.004), and protein kinetics did not differ between interventions. C-reactive peptide (mg/L) was elevated in CAT compared with CTR (30.57 ± 4.08 vs 1.03 ± 0.19, p<0.001). Energy expenditure increased by 6% during CAT compared with CTR (1869 ± 94 vs 1756 ± 58, p = 0.04), CAT having higher lipid oxidation rates (p = 0.01) and lower glucose oxidation rates (p = 0.03). Lipopolysaccharide caused varying abdominal discomfort 2 hours post-injection, which had disappeared the following day.ConclusionWe found that combined systemic inflammation, fasting and bed rest induced marked insulin resistance and increased energy expenditure and lipolysis, rendering this controlled experimental model suitable for anti-catabolic intervention studies, mimicking clinical conditions.
Highlights
Hospitalisation is accompanied by muscle wasting and altered metabolism due to the catabolic combination of immobilisation, inflammation and calorie restriction [1,2,3]
The median palmitate flux was higher during CAT than in CTR (257.0 (161.7 365.4) vs 131.6 (92.3 189.4), p = 0.004), and protein kinetics did not differ between interventions
C-reactive peptide was elevated in CAT compared with CTR (30.57 ± 4.08 vs 1.03 ± 0.19, p
Summary
Hospitalisation is accompanied by muscle wasting and altered metabolism due to the catabolic combination of immobilisation, inflammation and calorie restriction [1,2,3]. Human controlled studies have used prolonged periods of fasting to explore the effects of low/non energy intake [5], bed rest to examine the catabolic effects of immobilization [6], and systemic lipopolysaccharide (LPS) exposure to investigate the acute catabolic effects of inflammation [4]. These models have focused on the isolated effects of these catabolic stimulants even though most catabolic states are caused by a combination of all three components. Abdominal discomfort and nausea have precluded administration of oral interventions acutely after LPS-induced systemic inflammation
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