Sleep Apnea and Mechanisms of Insulin Resistance

肥胖症在美国正达到流行病的程度，并由于广泛的 疾病的范围。肥胖最常见的两种并发症是睡眠呼吸暂停(SA)和2型 糖尿病，以及最近的证据表明，间歇性低氧(IH)和睡眠碎片(SF) 确定睡眠呼吸暂停可独立导致糖耐量减低和胰岛素抵抗 加速肥胖导致糖尿病的过程。IH和SF可能都会影响 代谢功能，目前提议的主要目的是描绘途径和 IH和SF导致糖耐量异常和胰岛素抵抗的机制。我们建议 瘦素和黑素皮质素途径的信号受损，这两条途径通常调节食物的摄取、代谢， 在IH存在的情况下，外周组织的胰岛素敏感性可导致胰岛素抵抗。此外， 我们认为SF可以通过不同的途径刺激胰岛素抵抗，从而产生胰岛素抵抗。 交感-肾上腺轴。我们的方法是检验验证的IH和SF模型在正常人中的效果 和肥胖/糖尿病倾向的近交系小鼠，并利用特定的转基因和基因敲除小鼠来探索 瘦素、黑素皮质素和肾上腺素能通路的功能意义。我们将采用最先进的技术 胰岛素敏感性(高胰岛素正血糖钳夹)、血糖测定的临床参数 耐量(静脉葡萄糖耐量试验)和肝脏葡萄糖输出量。具体来说，我们建议： (1)测定野生型和瘦素缺陷小鼠的胰岛素抵抗程度 暴露于IH和SF，以及中枢和外周应用外源性瘦素是否具有保护作用 在IH和SF期间对抗胰岛素抵抗。 (2)研究内源性或外源性阻断黑素皮质素途径是否导致胰岛素 在IH和SF期间的抗性。 (3)探讨α-肾上腺素能受体和皮质酮增加胰岛素的作用。 IR和/？3-肾上腺素能受体可降低IH和SF所致的胰岛素抵抗。 拟议的实验将阐明IH和SF导致胰岛素的致病途径。 外周组织中的抵抗力，并确定降低睡眠呼吸暂停风险的潜在干预部位 加速肥胖患者胰岛素抵抗的进展。

Obesity is reaching epidemic proportions in the U.S. and poses a serious public health burden due to a wide range of cdmorbidities. Two of the most common complications of obesity are sleep apnea (SA) and type 2 diabetes, and recent evidence suggests that the intermittent hypoxia (IH)and sleep fragmentation (SF) that characterize sleep apnea may independently cause glucose intolerance and insulin resistance and accelerate the process by which obesity leads to diabetes. Potentially both the IH and SF may affect metabolic function, and the major purpose of the current proposal is to delineate the pathways and mechanisms through which IH and SF lead to glucose intolerance and insulin resistance. We propose that impaired signaling of leptin and melanocortin pathways, which normally regulate food intake, metabolism, and insulin sensitivity of peripheral tissues can cause insulin resistance in the presence of IH. Furthermore, we propose that SF can act through different pathways to produce insulin resistance by stimulating the sympathoadrenal axis. Our approach is to examine the effects of validated models of IH and SF in normal and obesity/diabetic prone inbred mice, and to utilize specific transgenic and knockout mice to explore the functional significance of leptin, melanocortin, and adrenergic pathways. We will employ state-of-the-art clinical parameters for measurement of insulin sensitivity (hyperinsulinemic euglycemic clamp), glucose tolerance (intravenous glucose tolerance test), and hepatic glucose output. Specifically, we propose: (1) To determine the magnitude of insulin resistance that occurs in wildtype and leptin-deficient mice exposed to IH and SF, and whether central and peripheral administration of exogenous leptin protects against insulin resistance during IH and SF. (2) To investigate whether endogenous or exogenous blockade of the melanocortin pathway leads to insulin resistance during IH and SF. (3) To examine the role of the role of a-adrenergic receptors and corticosterone increasing insulin resistance, and /?3-adrenergic receptors decreasing insulin resistance in response to IH and SF. The proposed experiments will elucidate causative pathways through which IH and SF lead to insulin resistance in peripheral tissues and identify potential intervention sites for reducing the risk of sleep apnea accelerating the progression of insulin resistance in obese patients.