BEDREST Determination of the time-course of the development of insulin resistance, and associated molecular and muscular adaptations during prolonged

该项目将为未来的转化研究提供基础，以对抗不活动。身体活动减少严重影响生活质量，并增加发病率和死亡率。目前世界卫生组织（WHO）对身体活动的建议是，18-64岁的人每周至少进行150分钟的中等强度有氧运动，或至少进行75分钟的高强度有氧运动。然而，据世卫组织估计，2009年全世界有17%的成年人没有达到这一标准，到2012年，这一数字已增加到31%，表明世界范围内的公共卫生问题正在恶化。世卫组织的估计惊人地说明了这一点，即缺乏身体活动现在是全球第四大死亡原因，占全球死亡人数的6%。此外，有证据表明，缺乏身体活动是许多现代代谢性疾病的病因，包括肥胖、胰岛素抵抗、2型糖尿病、血脂异常和高血压等，这说明了缺乏身体活动与发病率之间的联系；世卫组织指出，缺乏身体活动是27%的糖尿病和30%的缺血性心脏病病例的主要原因。除了久坐不动的生活方式导致日常身体活动减少外，受伤、疾病、残疾和年老也会导致长期缺乏身体活动。综上所述，与缺乏活动有关的健康失调日益普遍，不仅在医疗费用方面，而且在改善生活质量方面，都造成了巨大的经济负担。胰岛素抵抗可以定义为我们的肌肉无法对激素胰岛素做出反应以降低血糖水平，也是2型糖尿病、心血管疾病、肌肉骨骼疾病和某些癌症发展的主要危险因素。我们知道，与不运动相关的肌肉质量损失和肌肉脂肪积累是胰岛素抵抗的主要原因，但我们不知道这些事件的时间过程或机制基础。此外，我们不知道45岁以上肌肉质量的加速损失是否比不运动本身对维持胰岛素敏感性造成了额外的负担，如果是这样，这代表了多大程度的代谢损害。因此，清楚地了解生理适应对缺乏运动的程度和时间关系，对于制定目前缺失的有效对策至关重要。在这方面，卧床休息模型可以获得关于短期和长期不运动对人体胰岛素抵抗的生理影响的有价值的见解，因此本提案的目的是利用60天卧床休息的人体研究设计来阐明以下问题：(i)卧床休息期间腿部和全身胰岛素抵抗的发生率是多少？（ii）是否随着时间的推移而恶化？7天卧床休息的研究表明并非如此，但缺少时间数据（特别是腿部与全身）（iii）固定诱发肌肉胰岛素抵抗的生理和分子驱动因素是什么，以及每种因素随时间的相对变化？（四）在60天的卧床休息过程中，与萎缩、燃料代谢有关的肌肉基因表达的时间变化是什么？与蠕虫在太空飞行期间已知的变化基因是否存在共性？(v)含有多种成分的干预鸡尾酒如何调节肌肉胰岛素抵抗、碳水化合物氧化和线粒体功能，影响这些测量参数？（vi）卧床休息后，腿部和全身胰岛素敏感性的恢复速度以及相关的生理和分子变化是如何调节的？

This project will provide the foundation for future translational research to combat inactivity. Reduced physical activity impacts heavily on quality of life, and increases both morbidity and mortality. The current World Health Organisation (WHO) recommendation for physical activity is set at a minimum of 150 minutes of moderate intensity aerobic activity per week in individuals aged 18-64, or at least 75 minutes of vigorous intensity aerobic physical activity. However, it has been estimated by WHO that in 2009 17% of adults worldwide failed to meet this guideline, and by 2012 this figure had increased to 31%, pointing to a worsening world-wide public health problem. This point is startlingly illustrated by the WHO estimation that physical inactivity is now the fourth leading cause of death worldwide, accounting for 6% of deaths globally. Furthermore, the association between physical inactivity and morbidity is illustrated by evidence suggesting that physical inactivity is causative in the development of many modern metabolic diseases including obesity, insulin resistance, type 2 diabetes, dyslipidemia and hypertension, amongst others; with physical inactivity being cited by WHO as the principle cause of 27% of diabetes and 30% of ischaemic heart disease cases. In addition to the reductions in daily physical activity brought about by a sedentary lifestyle, prolonged periods of physical inactivity occur as a consequence of injury, disease, disabilities and advanced age. Taken together, the increased prevalence of health disorders related to inactivity exerts a substantial economic burden, not only in medical care costs but also the cost of improving quality of life. Skeletal muscle Insulin resistance can be defined as the inability of our muscles to respond to the hormone insulin to lower blood glucose levels, and is also major risk factor for the development of type 2 diabetes, cardiovascular disease, musculoskeletal disorders and some cancers. We know that the inactivity-associated loss of muscle mass and muscle fat accumulation is a major cause of insulin resistance, but we do not know the time course or mechanistic basis of these events. Furthermore, we do not know whether the accelerated loss of muscle mass that occurs beyond 45 years of age represents an added burden to maintaining insulin sensitivity than that from inactivity per se, and if it does, what magnitude of metabolic insult this represents. Thus, a clear understanding of the extent and temporal relationships of physiological adaptation to physical inactivity is therefore vital in the development of effective countermeasures that are at present missing. In this regard, bed-rest models enable valuable insight to be obtained regarding the physiological impact of short and long-term physical inactivity on human insulin resistance, and so the aim of the present proposal is to utilise a 60-day bed-rest human study design to elucidate the following:(i) What is the rate of onset of leg and whole body insulin resistance during bed rest?(ii) Does it worsen over time? Seven day bed rest studies suggest not, but temporal data are missing (and particularly leg vs whole body)(iii) What are the physiological and molecular drivers of immobilization induced muscle insulin resistance, and the relative change in the contribution of each over time?(iv) What are the temporal changes in muscle gene expression over the course of 60 days bed rest linked to atrophy, fuel metabolism, and is there commonality with genes known to change during space flight in worms?(v) How does an intervention cocktail containing a number of ingredients that can modulate muscle insulin resistance, carbohydrate oxidation and mitochondrial function affect these measurement parameters? (vi) What is the rate of restoration of leg and whole body insulin sensitivity and the associated physiological and molecular changes post bed-rest, and how is this modulated by muscular contraction?