Altered glucose homeostasis by sleep impairment

描述（由申请人提供）： 阻塞性睡眠呼吸暂停（OSA）是一种以睡眠期间反复发作的上呼吸道阻塞为特征的病症，影响2- 5%的普通人群。大量的临床数据已经清楚地证实了OSAS、肥胖和糖耐量受损之间的联系。如果阻塞性睡眠呼吸暂停综合征和糖耐量受损之间的这种联系是因果关系，那么睡眠呼吸暂停可能是发展为II型糖尿病的更重要的危险因素之一。我们将在OSAS小鼠模型中使用睡眠呼吸暂停的两个主要特征，即间歇性缺氧和睡眠碎片，以确定睡眠呼吸暂停的成分是否能够导致葡萄糖稳态的破坏。大多数关于睡眠障碍和血糖调节的研究都集中在胰岛素抵抗的发展上。然而，除非胰腺β细胞的胰岛素分泌也至少部分失败，否则II型糖尿病不能发展。睡眠呼吸暂停和间歇性缺氧会产生氧化应激，β细胞对氧化应激非常敏感。为了确定睡眠呼吸暂停是否会对β细胞造成压力或损害，我们将测量胰岛素的合成和分泌，并测试β细胞是否表现出压力的迹象，特别是氧化应激。为了确定氧化应激是否在呼吸暂停引起的葡萄糖调节损伤中起关键作用，我们将测试抗氧化转基因的过表达是否提供对间歇性缺氧或睡眠片段的保护。我们的初步结果表明，肥胖小鼠对睡眠中断对葡萄糖耐量和胰岛素分泌的不利影响比瘦小鼠更敏感。由于肥胖和睡眠呼吸暂停是常见的和相关的，许多患者表现出两种病理。这可能对葡萄糖稳态产生协同损害。我们将测试OSAS对肥胖和瘦小鼠的同类品系的影响。

DESCRIPTION (provided by applicant): Obstructive sleep apnea (OSAs), a condition characterized by repeated episodes of upper airway obstruction during sleep, affects 2-5 % of the general population. Extensive clinical data has clearly established an association between (OSAS), obesity and impaired glucose tolerance. If this association between OSAS and impaired glucose tolerance is causal than sleep apnea may be one of the more important risk factors for development of Type II diabetes. We will use two primary characteristics of sleep apnea, intermittent hypoxia and sleep fragmentation, in mouse models of OSAS to determine if components of sleep apnea are capable of causing disruption of glucose homeostasis. Most studies of sleep disorders and glucose regulation have focused on the development of insulin resistance. However, Type II diabetes cannot develop unless there is also at least partial failure of insulin secretion by pancreatic beta cells. Sleep apnea and intermittent hypoxia produce oxidative stress and beta cells are exquisitely sensitive to oxidative stress. To determine whether sleep apnea stresses or damages the beta cell we will measure insulin synthesis and secretion and test if beta cells exhibit signs of stress, particularly oxidative stress. To establish whether oxidative stress plays a critical role in apnea induced damage to glucose regulation we will test whether overexpression of antioxidant transgenes provide protection from intermittent hypoxia or sleep fragmentation. Our preliminary results indicate that obese mice are much more sensitive to the detrimental effects of sleep disruption on glucose tolerance and insulin secretion than are lean mice. Since obesity and sleep apnea are common and associated, many patients exhibit both pathologies. This may produce synergistic damage to glucose homeostasis. We will test the effect of OSAS on congenic strains of obese and lean mice.