Sleep Disordered Breathing and Glucose Regulation

描述(由申请人提供)： 睡眠呼吸障碍(SDB)和2型糖尿病是严重的 与肥胖相关的健康问题。最近的流行病学研究表明 研究表明，SDB可能与胰岛素抵抗和血糖调节有关， 不受肥胖的影响。然而，SDB可能影响的机制 葡萄糖和胰岛素的调节是未知的。据推测，间歇性的 低氧(IH)和SDB睡眠碎片化可能影响血糖调节。 低氧可通过上调胰岛素-葡萄糖轴的表达影响胰岛素-葡萄糖轴 低氧诱导因子-1α(HIF-1α)激活血管内皮细胞的表达 葡萄糖转运蛋白，导致血糖水平下降。论 另一方面，睡眠碎片可能会导致压力和胰岛素的激活。 反调节激素，如皮质醇和肾上腺素，导致 血糖水平升高。在我们的初步数据中，我们表明IH 引起双相反应，包括血糖水平的下降 一周后，三周后血糖升高 曝光。此外，代谢荷尔蒙瘦素的缺失导致 在对IH的反应中处于更明显的高血糖阶段 野生型老鼠。我们的主要假设是，SDB会导致两个阶段的变化 葡萄糖动态平衡。早期血糖下降是由于缺氧引起的。 HIF-1α激活和葡萄糖转运蛋白上调。已故的 血糖升高是由于睡眠碎片激活了胰岛素 反调节荷尔蒙，这种作用被瘦素加剧 缺乏症。为了验证我们的假设，我们将使用 IH和SDB小鼠模型。我们将使用野生型小鼠，带有和 没有饮食肥胖，以及瘦素缺乏的ob/ob小鼠和转基因 HIF-1α小鼠。在具体目标一中，我们将确定-九个时间进程 血糖、血清胰岛素、胰岛素逆调节激素的变化， 和组织葡萄糖转运蛋白在瘦小鼠和肥胖小鼠的IH过程中。具体而言 目的2我们将分离高血糖症和睡眠片断对血糖的影响 监管。在具体目标I中，我们将具体研究HIF的作用- 1转基因小鼠血糖反应中的α和瘦素。因此， 这项研究将从机制上考察SDB如何影响血糖调节， 这可能会对SDB和糖尿病这两个领域产生重大影响。

DESCRIPTION( provided by applicant): Sleep Disordered Breathing (SDB) and type 2 diabetes mellitus are serious health problems associated with obesity. Recent epidemiological studies have shown that SDB may be linked to insulin resistance and glucose regulation, independent of obesity. However, the mechanisms by which SDB may affect glucose and insulin regulation are unknown. Putatively, the intermittent hypoxia (IH) and sleep fragmentation of SDB may impact on glucose regulation. Hypoxia could affect the insulin-glucose axis through upregulation of hypoxia-inducible factor- I alpha (HIF- 1alpha) which activates expression of glucose transporters, resulting in decreased blood glucose levels. On the other hand, sleep fragmentation could lead to stress and activation of insulin counter-regulatory hormones, such as cortisol and epinephrine, resulting in increased blood glucose levels. In our Preliminary Data we show that IH causes a biphasic response consisting of a decrease in blood glucose levels after one week followed by a rise in blood glucose after three weeks of exposure. Furthermore, the absence of the metabolic hormone leptin resulted in a more pronounced hyperglycemic phase in response to IH compared to wildtype mice. Our major hypothesis is that SDB causes biphasic changes in glucose homeostasis. The early decrease in blood glucose is due to hypoxic activation of HIF- 1alpha and upregulation of glucose transporters. The late increase in blood glucose is due to sleep fragmentation activating insulin counter-regulatory hormones, and this effect is exacerbated by leptin deficiency. In order to test our hypotheses we will utilize a mouse model of IH as well as a mouse model of SDB. We will use wildtype mice, with and without dietary obesity, as well as leptin deficient ob/ob mice and transgenic HIF- 1alpha mice. In Specific Aim I we will determine-nine the time course of changes in blood glucose, serum insulin, insulin counterregulatory hormones, and tissue glucose transporters during IH in lean and obese mice. In Specific Aim 2 we will separate the effects of IH and sleep fragmentation on glucose regulation. In Specific Aim I we will specifically examine the role of HIF- 1alpha and leptin in glucose responses to IH using transgenic mice. Thus, this study will examine mechanistically how SDB affects glucose regulation, which could have a significant impact on both fields of SDB and diabetes.