睡眠不足可诱发脂肪细胞胰岛素抵抗

《内科学年鉴》10月6日发表的一项研究显示，睡眠剥夺可导致健康体瘦年轻成人脂肪细胞的胰岛素敏感性降低30%(Ann. Intern. Med. 2012;157:549-57)。

该研究从社区招募了7名健康的体瘦年轻成人，男性6名，女性1名，平均年龄为23.7岁(18~30岁)。所有受试者的常规睡眠时间为7.5~8.5 h/晚。对所有受试者进行夜间多导睡眠图检查，以确保他们无睡眠障碍，并进行标准糖耐量试验，以排除任何隐性的胰岛素代谢障碍。此外，还进行标准实验室检查，以排除任何其他可能影响睡眠或代谢的问题。

随后，在以下两种实验性睡眠条件下按随机顺序对受试者进行评估：每晚正常睡眠8.5 h连续4晚，以及每晚限制性睡眠4.5 h连续4晚。在实验期间，受试者均在医院留宿，并且在这两种睡眠条件下均采用相同的严格控制饮食。

在睡眠实验结束时，采集腹部皮下脂肪组织，体外测定磷酸化Akt在胰岛素剂量不断增加情况下的反应。此外，还频繁采集静脉血进行糖耐量试验，评估全身胰岛素敏感性。

受试者在正常睡眠条件下的平均睡眠时间为8.78 h/晚，在限制性睡眠条件下为4.35 h/晚。快动眼睡眠量在后一种睡眠条件下降低56.8%。如同预期，正常睡眠后，胰岛素激发导致磷酸化Akt呈剂量依赖性增加。相反，在剥夺部分睡眠后，胰岛素激发导致磷酸化Akt降低30%。此外，与正常睡眠相比，在剥夺部分睡眠后，全身胰岛素敏感性降低16%。

研究者表示，该研究在正常睡眠者与睡眠剥夺者之间观察到的磷酸化Akt差异与既往研究在肥胖者和体瘦者之间及糖尿病患者和非糖尿病者之间观察到的结果一致，表明长期睡眠剥夺或睡眠障碍者脂肪细胞胰岛素信号的受损可能会对代谢产生重要的不良影响。从临床角度来看，该研究进一步证明，睡眠不足可导致代谢障碍发生或恶化。传统观念认为睡眠只对大脑功能的恢复有帮助，但该研究表明睡眠在保持多种外周细胞的功能完整性和全身能量稳态方面也发挥重要作用。

该研究的局限性在于采用单中心设计、样本量非常小且只纳入1名女性。因此未来需在样本量更大且更多样的人群中加以验证。

该研究获国立卫生研究院资助。研究者声明无经济利益冲突。

随刊述评：传统睡眠观念受到挑战

英国华威大学的Francesco P. Cappuccio博士和Michelle A. Miller博士表示，该研究揭示了睡眠剥夺是如何直接导致糖尿病和肥胖的。传统观点认为睡眠的主要功能是恢复中枢神经系统功能，而该研究表明睡眠还可影响代谢、脂肪组织、心血管功能等机体功能。研究结果也强调，未来有必要探讨那些限制睡眠时间的因素，并开发有助于改善个体和社会总体健康的策略(Ann. Intern. Med. 2012;157:593-4)。

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By: MARY ANN MOON, Clinical Endocrinology News Digital Network

Sleep deprivation caused a 30% decline in the insulin sensitivity of fat cells of healthy, lean young adults, according to a study in the Oct. 6 issue of Annals of Internal Medicine.

Restricting sleep for 4 nights markedly impaired the phosphorylation of Akt within the adipocytes in subcutaneous fat, which is a crucial early step in the pathway that mediates most of insulin's metabolic action. "This finding identifies for the first time a molecular mechanism that may be involved in the reduction in total-body insulin sensitivity consistently observed in multiple laboratory studies of partial sleep deprivation in healthy adults," said Josiane L. Broussard, Ph.D., and her associates at the University of Chicago.

Moreover, "our finding of marked alterations in adipocyte function after experimental sleep restriction challenges the widely held belief that the primary function of sleep is the restoration of central nervous system function and suggests that sleep may play an equally important role in peripheral energy metabolism," they noted.

Insufficient sleep is known to raise the risk of metabolic disturbances, particularly insulin resistance, obesity, and type 2 diabetes. But "to our knowledge, no studies to date have linked sleep restriction to alterations in molecular metabolic pathways in any peripheral human tissue." Dr. Broussard and her colleagues examined whether experimental sleep restriction would reduce insulin sensitivity in subcutaneous fat, "a peripheral tissue that is a key site of insulin action and plays a pivotal role in energy metabolism as well as in the communication of energy balance to the brain."

Six men and one woman aged 18-30 years (mean age 23.7 years) who were healthy and lean were selected from the community as study subjects. All reported routine sleep times of 7.5-8.5 hours/night. All underwent overnight polysomnography to ensure they had no sleep disorders, standard glucose tolerance testing to rule out any occult disorders of insulin metabolism, and standard laboratory tests to rule out any other problem that could affect either sleep or metabolism.

These subjects were then assessed under two experimental sleep conditions in randomized order: after 4 consecutive nights of 8.5 hours of normal sleep and after 4 consecutive nights of 4.5 hours of restricted sleep. The subjects lived as sedentary inpatients during these experiments, with strictly controlled diets that were identical under the two sleep conditions.

At the conclusion of the sleep periods, abdominal subcutaneous fat tissue was sampled for in vitro measurement of phosphorylated Akt in response to increasing doses of insulin. Total body insulin sensitivity also was assessed using frequently sampled intravenous glucose tolerance tests.

The study subjects averaged 8.78 hours of sleep per night under the normal sleep condition and 4.35 hours under the restricted sleep condition. The amount of REM sleep was reduced by 56.8% in the latter condition.

After normal sleep, insulin provocation caused dose-dependent increases in phosphorylated Akt, as expected. In dramatic contrast, sleep restriction consistently induced an approximately 30% reduction in phosphorylated Akt in response to insulin provocation.

In addition, total-body insulin sensitivity was reduced by 16% after partial sleep deprivation, compared with normal sleep.

The 30% decline "lies within the range of the difference in insulin sensitivity in adipocytes from obese vs. lean participants and from diabetic patients vs. nondiabetic participants" in previous studies. "Thus, the impairment of insulin signalling in adipocytes from persons who are chronically sleep-deprived or have sleep disorders is likely to have important metabolic consequences," Dr. Broussard and her associates wrote (Ann. Intern. Med. 2012;157:549-57).

"From a clinical standpoint, our study provides additional evidence that insufficient sleep may contribute to the development of or exacerbate metabolic disorders." But the findings also "shed novel light on the still-elusive function of sleep, traditionally conceptualized as necessary only for the brain, because they suggest that sleep plays an important role for the functional integrity of multiple peripheral cell types, as well as for whole-body energy homeostasis," they said.

This study was limited in that it was performed at a single center, involved a very small sample size and involved only one woman. "The findings will therefore need to be replicated in a larger and more diverse population," the researchers added.

This study was funded by the National Institutes of Health. The researchers reported having no relevant conflicts of interest.

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Findings Challenge the Accepted Wisdom Regarding Sleep

Dr. Broussard and her colleagues make a valuable contribution to our understanding of how sleep deprivation may directly contribute to diabetes and obesity, said Dr. Francesco P. Cappuccio and Dr. Michelle A. Miller.

Their findings also challenge "the traditional view that the primary purpose of sleep is confined to restorative effects on the CNS. [They] point to a much wider influence of sleep on bodily functions, including metabolism, adipose tissue, cardiovascular function, and possibly more," they said.

The results also highlight the need to address factors that limit sleep duration, as a strategy to improve the overall health of individuals as well as of society.

FRANCESCO P. CAPPUCCIO, M.D., and MICHELLE A. MILLER, PH.D., are at the University of Warwick, Coventry, England. They reported having no relevant conflicts of interest. These remarks were taken from their editorial accompanying Dr. Broussard’s report (Ann. Intern. Med. 2012;157:593-4).