EPISODIC HYPOXIA, HYPOTHALAMUS AND INSULIN RESISTANCE

阵发性缺氧、下丘脑和胰岛素抵抗

• 批准号: 6678637
• 负责人: LESZEK K KUBIN
• 金额: $ 39.94万
• 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/6678637
• 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）影响成年人群的3-5％。它的后果包括嗜睡，生产力降低和生活质量降低。 OSA与高血压有因果关系，可能导致2型糖尿病。根据现有的证据和我们的初步数据，我们假设OSA的主要致病因素慢性间歇性缺氧（IH）增加了中央肾上腺素能活性。反过来，这改变了葡萄糖代谢的下丘脑控制，并导致类似糖尿病的疾病。我们进一步假设下丘脑的相关中心变化是由去甲肾上腺素能和GABA - 迫切机制介导的，并发生在表达转录因子STAT和SOCS的细胞中，这些细胞和SOCS从细胞因子，胰岛素和瘦素信号通路下游进行操作。为了检验我们的假设，我们计划研究与控制IH大鼠的葡萄糖代谢相关的中央和外围细胞信号传导的改变。在特定的目标1中，我们将确定在不同时期内接触IH是否会导致MRNA和蛋白质水平的进行性和区域特定的变化，用于转录因子和参与中央代谢对照的受体（STAT，SOCS和胰岛素受体底物，瘦素和肾上腺素能受体，GABAA受体，GABAA受体亚基），以及是否会持久变化IH IH的术语。我们将在区域水平上量化mRNA变化，通过免疫组织化学研究蛋白质的变化，并使用静脉葡萄糖耐受性检验和最小模型分析获得葡萄糖动力学中系统性改变的平行度量。在特定的目标2中，我们将确定是否类似于其对动脉高血压发展的影响，颈动脉身体神经支配阻止了类似糖尿病的变化的发展。在特定的目标3中，我们将测试肾上腺素能受体激动剂的急性局部显微注射是否会导致不同的下丘脑核会导致转录因子和/或受体类似于IH引起的受体的表达改变。在特定的目标4中，我们将测试慢性局部输注或使用肾上腺素或血管紧张素受体拮抗剂的全身治疗，以防止IH诱导的糖尿病样变化。提出的实验将对IH与胰岛素抵抗的中心机制之间的关系进行全面评估，并评估治疗干预措施的潜力。