Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
STENO Diabetes Center, Aarhus University Hospital, Aarhus, Denmark.
PLoS One. 2020 Nov 5;15(11):e0241274. doi: 10.1371/journal.pone.0241274. eCollection 2020.
Inflammatory 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.
In 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.
Insulin 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.
We 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.
炎症性疾病具有分解代谢作用，与胰岛素抵抗、能量消耗增加、脂肪分解和肌肉蛋白质流失有关。这些代谢适应的主要促成因素是炎症、营养不良和固定不动。缺乏包含住院治疗这些核心要素的对照实验模型。本研究的目的是验证这种人类实验模型。
在一项随机交叉设计中，六名健康年轻男性接受了以下两种处理：（i）过夜禁食（对照），或（ii）全身内毒素（1ng/kg）暴露加上 36 小时禁食和卧床休息（CAT）。CAT 与对照相比胰岛素敏感性的差异是主要结果，通过高胰岛素正葡萄糖钳夹来确定。输注棕榈酸、葡萄糖、尿素、苯丙氨酸和酪氨酸示踪剂来估计干预期间的代谢变化。间接量热法用于估计能量消耗和底物氧化。
与对照相比，CAT 时胰岛素敏感性降低 41%（M 值，mg/kg/min）：4.3±0.2 比 7.3±1.3，p<0.05。与对照相比，CAT 时棕榈酸流量（μmol/min）中位数（最小-最大）更高（257.0（161.7-365.4）比 131.6（92.3-189.4），p=0.004），并且两种干预措施之间的蛋白质动力学没有差异。与对照相比，CAT 时 C 反应蛋白（mg/L）升高（30.57±4.08 比 1.03±0.19，p<0.001）。与对照相比，CAT 时能量消耗增加 6%（1869±94 比 1756±58，p=0.04），CAT 时脂肪氧化率更高（p=0.01），葡萄糖氧化率更低（p=0.03）。脂多糖注射后 2 小时引起不同程度的腹部不适，第二天消失。
我们发现，全身性炎症、禁食和卧床休息联合作用会导致明显的胰岛素抵抗以及能量消耗和脂肪分解增加，使这种对照实验模型适合抗分解代谢干预研究，模拟临床情况。
