Circadian misalignment induces fatty acid metabolism gene profiles and induces insulin resistance in human skeletal muscle.

Circadian misalignment, such as in shift work, has been associated with obesity and type 2 diabetes, however, direct effects of circadian misalignment on skeletal muscle insulin sensitivity and muscle molecular circadian clock have never been investigated in humans. Here we investigated insulin sensitivity and muscle metabolism in fourteen healthy young lean men (age 22.4 ± 2.8 years; BMI 22.3 ± 2.1 kg/m2 [mean ± SD]) after a 3-day control protocol and a 3.5-day misalignment protocol induced by a 12-h rapid shift of the behavioral cycle. We show that circadian misalignment results in a significant decrease in peripheral insulin sensitivity due to a reduced skeletal muscle non-oxidative glucose disposal (Rate of disappearance: 23.7 ± 2.4 vs. 18.4 ± 1.4 mg/kg/min; control vs. misalignment; p=0.024). Fasting glucose and FFA levels as well as sleeping metabolic rate were higher during circadian misalignment. Molecular analysis of skeletal muscle biopsies revealed that the molecular circadian clock was not aligned to the new behavourial rhythm, and microarray analysis revealed the human PPAR pathway as a key player in the disturbed energy metabolism upon circadian misallignement. Our findings may provide a mechanism underlying the increased risk of type 2 diabetes among shift workers. Microarray analysis was performed on skeletal muscle biopsies (m. vastus lateralis) from healthy lean young men in a circadian misalignment study.

诸如轮班工作所致的昼夜节律紊乱（circadian misalignment），已被证实与肥胖及2型糖尿病相关，但此前尚未在人体中探究昼夜节律紊乱对骨骼肌胰岛素敏感性及肌肉分子生物钟的直接影响。本研究纳入14名健康年轻瘦体型男性（年龄22.4±2.8岁；体质量指数BMI 22.3±2.1 kg/m²，数据为均值±标准差），分别实施3天对照方案与3.5天由行为周期12小时快速移位诱导的节律紊乱方案，检测受试者的胰岛素敏感性与肌肉代谢指标。研究结果显示，昼夜节律紊乱会引发外周胰岛素敏感性显著下降，这一现象源于骨骼肌非氧化葡萄糖处置能力降低（葡萄糖消失速率：对照组23.7±2.4 vs 紊乱组18.4±1.4 mg/kg/min；p=0.024）。昼夜节律紊乱期间，受试者的空腹血糖、游离脂肪酸（FFA）水平以及睡眠代谢率均有所升高。对骨骼肌活检样本的分子分析表明，肌肉分子生物钟并未与新的行为周期同步；而基因芯片（microarray）分析显示，人类过氧化物酶体增殖物激活受体（PPAR）通路是昼夜节律紊乱后能量代谢紊乱的关键调控通路。本研究结果或可阐明轮班工作人群2型糖尿病风险升高的潜在分子机制。本昼夜节律紊乱研究中的基因芯片分析，其骨骼肌活检样本取自股外侧肌（m. vastus lateralis），均来自健康瘦体型年轻男性。