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 与肥胖有关的健康问题。 最近的流行病学研究表明， 显示SDB可能与胰岛素抵抗和葡萄糖调节有关， 与肥胖无关。 然而，SDB可能影响的机制 葡萄糖和胰岛素调节是未知的。 间歇性，间歇性 SDB的缺氧（IH）和睡眠片段化可能影响血糖调节。 缺氧可通过上调胰岛素-葡萄糖轴 低氧诱导因子- I α（HIF-1 α），其激活 葡萄糖转运蛋白，导致血糖水平降低。 上 另一方面，睡眠碎片可能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 引起包括血糖水平降低的双相反应 一周后血糖升高，三周后血糖升高 exposure. 此外，缺乏代谢激素瘦素导致 在对IH的反应中， 野生型小鼠 我们的主要假设是，SDB导致双相变化， 葡萄糖稳态 血糖早期下降是由于缺氧 HIF-1 α的激活和葡萄糖转运蛋白的上调。 末 血糖升高是由于睡眠片段激活胰岛素 反调节激素，这种作用是由瘦素加剧 缺陷 为了验证我们的假设，我们将利用小鼠模型， IH以及SDB的小鼠模型。 我们将使用野生型小鼠， 没有饮食性肥胖，以及瘦素缺乏的ob/ob小鼠和转基因小鼠。 HIF-1 α小鼠。 在具体目标I中，我们将确定 血糖、血清胰岛素、胰岛素反调节激素的变化， 和组织葡萄糖转运蛋白。 在特定 目的2我们将分离间歇性睡眠和睡眠片段对血糖的影响 调控 在具体目标I中，我们将专门研究HIF的作用- 1 α和瘦素在葡萄糖对IH反应中的作用。 因此，在本发明中， 本研究将从机理上研究SDB如何影响葡萄糖调节， 这可能对SDB和糖尿病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.