EPISODIC HYPOXIA, HYPOTHALAMUS AND INSULIN RESISTANCE

阵发性缺氧、下丘脑和胰岛素抵抗

• 批准号: 6787159
• 负责人: LESZEK K KUBIN
• 金额: $ 35.89万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6787159
• 关键词: adrenergic receptor; angiotensin receptor; carotid body; glucose metabolism; glucose tolerance test; hypothalamus; immunocytochemistry; insulin receptor; insulin sensitivity /resistance; laboratory rat; leptin; norepinephrine; polymerase chain reaction; receptor expression; respiratory hypoxia; sleep apnea; transcription factor

DESCRIPTION (provided by applicant): Obstructive sleep apnea (OSA) affects 3-5% of the adult population. Its consequences include sleepiness, reduced productivity and a low quality of life. OSA is causally associated with hypertension and may lead to type 2 diabetes. Based on existing evidence and our preliminary data, we hypothesize that chronic intermittent hypoxia (IH), a major pathogenic factor in OSA, increases central adrenergic activity. This, in turn, alters the hypothalamic control of glucose metabolism and leads to a diabetes-like condition. We further hypothesize that relevant central changes in the hypothalamus are mediated by noradrenergic and GABA-ergic mechanisms and occur in cells expressing transcription factors STAT and SOCS which operate downstream from the cytokine, insulin and leptin signaling pathways. To test our hypotheses, we plan to investigate alterations in the central and peripheral cellular signaling relevant for the control of glucose metabolism in rats exposed to IH. In Specific Aim 1, we will determine whether exposure to IH for different periods causes progressive and regionally specific changes of mRNA and protein levels for transcription factors and receptors involved in central metabolic control (STAT, SOCS and insulin receptor substrates, leptin and adrenergic receptors, GABAA receptor subunits), and whether the changes persist following termination of IH. We will quantify mRNA changes at the regional level, study protein changes with immunohistochemistry, and obtain parallel measures of systemic alterations in glucose kinetics using the intravenous glucose tolerance test and minimal model analysis. In Specific Aim 2, we will determine whether, similar to its effect on the development of arterial hypertension, carotid body denervation prevents the development of diabetes-like changes. In Specific Aim 3, we will test whether acute local microinjections of adrenergic receptor agonists into distinct hypothalamic nuclei cause alterations in the expression of transcription factors and/or receptors similar to those induced by IH. In Specific Aim 4, we will test whether chronic local infusion or systemic treatment with adrenergic or angiotensin receptor antagonists prevent the IH-induced diabetes-like changes. The proposed experiments will provide a comprehensive assessment of the relationship between IH and the central mechanisms of insulin resistance, and evaluate the potential for therapeutic interventions.

描述（由申请人提供）：阻塞性睡眠呼吸暂停 (OSA) 影响 3-5% 的成年人口。其后果包括嗜睡、生产力下降和生活质量低下。 OSA 与高血压有因果关系，并可能导致 2 型糖尿病。根据现有证据和我们的初步数据，我们假设慢性间歇性缺氧 (IH)（OSA 的主要致病因素）会增加中枢肾上腺素能活性。这反过来又改变了下丘脑对葡萄糖代谢的控制，并导致类似糖尿病的病症。我们进一步假设下丘脑的相关中枢变化是由去甲肾上腺素能和 GABA 能机制介导的，并发生在表达转录因子 STAT 和 SOCS 的细胞中，这些转录因子在细胞因子、胰岛素和瘦素信号通路的下游起作用。为了检验我们的假设，我们计划研究暴露于 IH 的大鼠中与葡萄糖代谢控制相关的中枢和外周细胞信号传导的变化。在具体目标 1 中，我们将确定不同时期暴露于 IH 是否会导致参与中枢代谢控制的转录因子和受体（STAT、SOCS 和胰岛素受体底物、瘦素和肾上腺素受体、 GABAA 受体亚基），以及 IH 终止后变化是否持续存在。我们将量化区域水平的 mRNA 变化，通过免疫组织化学研究蛋白质变化，并使用静脉内葡萄糖耐量试验和最小模型分析获得葡萄糖动力学系统变化的平行测量。在具体目标 2 中，我们将确定颈动脉体去神经支配是否可以预防类似糖尿病的变化，就像其对动脉高血压的影响一样。在具体目标 3 中，我们将测试将肾上腺素能受体激动剂急性局部显微注射到不同的下丘脑核中是否会导致转录因子和/或受体表达的改变，类似于 IH 诱导的改变。在具体目标 4 中，我们将测试肾上腺素能或血管紧张素受体拮抗剂的长期局部输注或全身治疗是否可以预防 IH 诱导的糖尿病样变化。拟议的实验将全面评估 IH 与胰岛素抵抗的中心机制之间的关系，并评估治疗干预的潜力。