阻塞性睡眠呼吸暂停低通气综合征患者胰岛素抵抗及与内源性大麻素系统关系的研究

发布时间：2018-06-04 05:03

  本文选题：阻塞性睡眠呼吸暂停低通气综合征 + 胰岛素抵抗　； 参考：《兰州大学》2016年博士论文

【摘要】：研究表明,阻塞性睡眠呼吸暂停低通气综合征(OSAHS)患者中糖代谢紊乱及糖尿病的发病率明显高于非OSAHS患者,进一步的研究提示OSAHS是胰岛素抵抗(IR)及糖尿病的独立危险因素。另外,IR及糖尿病的发生发展与内源性大麻素系统(ECS)关系密切,ECS的过度持久的活化是导致IR及糖尿病的重要原因,而抑制ECS活性的治疗可以有效缓解IR及糖尿病。但OSAHS患者ECS是否发生变化,以及ECS是否与OSAHS并发糖代谢紊乱有关,目前尚未见到相关的研究报道。因此,为了明确上述问题,特开展本研究,内容分为两个部分,第一部分为临床研究,初步探讨了OSAHS患者的糖代谢状态及其与ECS的关系,研究共纳入OSAHS患者64名(轻度18例,中度24例,重度22例),健康对照24例。测量受试者体块指数(BMI)、腰围、空腹血脂、血糖、血胰岛素、稳态模型评估的胰岛素抵抗指数(HOMA-IR)、多导睡眠图监测指标及外周血单个核细胞(PBMC)内源性大麻素Ⅰ型(CB1)受体蛋白表达情况。结果表明,相对于对照组,OSAHS患者糖代谢紊乱的发生率明显升高,且HOMA-IR、呼吸暂停低通气指数(AHI)及PBMC的CB1受体蛋白表达水平彼此之间呈显著正相关关系。为了进一步明确OSAHS对糖代谢及ECS影响的分子机制,本研究的第二部分内容通过建立OSAHS的动物模型,探索间歇性低氧(IH)对大鼠体重增长、糖代谢指标、骨骼肌细胞超微结构、骨骼肌胰岛素信号传导通路的关键组分GLUT4及ECS的重要组分CB1受体表达的影响。结果表明,IH状态下,大鼠体重增长减缓,HOMA-IR升高,同时大鼠骨骼肌细胞线粒体等超微结构出现损伤,骨骼肌细胞膜表面GLUT4、总GLUT4在基因和蛋白质水平表达均明显减少而CB1受体表达在基因和蛋白质水平均明显增加。相对于单纯IH组,在IH处置同时给予CB1受体拮抗剂利莫那班,则大鼠体重增长逐渐恢复正常,HOMA-IR下降,同时大鼠骨骼肌线粒体等超微结构损伤减轻,膜表面GLUT4、总GLUT4表达升高而CB1受体表达水平降低。本研究结果提示:OSAHS患者易于发生IR及糖代谢紊乱,且与伴随于OSAHS的ECS状态活化密切相关。IH引起的组织GLUT4表达减少及CB1受体表达增多可能是OSAHS引起糖代谢紊乱及IR的重要机制,CB1受体拮抗剂可以减轻IH导致的上述异常,有望在缓解OSAHS引起的糖代谢紊乱中起一定作用。
[Abstract]:The incidence of glucose metabolism disorder and diabetes mellitus in patients with obstructive sleep apnea hypopnea syndrome (OSAHS) is significantly higher than that in non-OSAHS patients. Further studies suggest that OSAHS is an independent risk factor for insulin resistance and diabetes. In addition, the occurrence and development of IR and diabetes mellitus are closely related to endogenous cannabinoid system. The excessive and persistent activation of endogenous cannabinoid system is an important cause of IR and diabetes, and the treatment of inhibiting the activity of ECS can effectively relieve IR and diabetes. However, whether ECS changes in patients with OSAHS and whether ECS is associated with OSAHS complicated with glucose metabolism disorder has not been reported. Therefore, in order to clarify the above problems, this study is divided into two parts. The first part is a clinical study, which preliminarily discusses the status of glucose metabolism and the relationship between glucose metabolism and ECS in patients with OSAHS. The study included 64 patients with OSAHS (18 mild cases). Moderate 24 cases, severe 22 cases, healthy control 24 cases. Body mass index (BMI), waist circumference, fasting blood lipid, blood glucose and insulin were measured. Homeostasis model was used to evaluate the expression of endogenous cannabinoid type I (CB1) receptor protein in HOMA-IRI, polysomnography and peripheral blood mononuclear cells (PBMCs). The results showed that the incidence of glucose metabolism disorder in OSAHS patients was significantly higher than that in the control group, and there was a significant positive correlation between HOMA-IRI, apnea hypopnea index (AHI) and CB1 receptor protein expression of PBMC. In order to further clarify the molecular mechanism of the effects of OSAHS on glucose metabolism and ECS, the second part of this study was to establish an animal model of OSAHS to explore the effects of intermittent hypoxia on body weight, glucose metabolism and ultrastructure of skeletal muscle cells in rats. Effects of key components of insulin signal transduction pathway in skeletal muscle on the expression of GLUT4 and CB1 receptor, an important component of ECS. The results showed that under the condition of IH, the weight gain of rats slowed down the increase of HOMA-IR, and the ultrastructure of mitochondria of skeletal muscle cells was damaged. GLUT4, total GLUT4 expression at gene and protein level were significantly decreased, while CB1 receptor expression was significantly increased at gene and protein levels on skeletal muscle cell membrane. Compared with the pure IH group, the weight gain of the CB1 receptor antagonist rimonabine was gradually reduced, and the damage of mitochondria and mitochondria of skeletal muscle was reduced, compared with that in the pure IH group. On the surface of GLUT4, the expression of total GLUT4 increased and the expression of CB1 receptor decreased. The results of this study suggest that patients with OSAHS are prone to IR and glucose metabolism disorders. The decrease of GLUT4 expression and the increase of CB1 receptor expression in tissues induced by ECS state activation associated with OSAHS may be an important mechanism of glycometabolism and IR induced by OSAHS. CB1 receptor antagonist can attenuate these abnormalities induced by IH. It is expected to play a role in alleviating the disorder of glucose metabolism caused by OSAHS.
【学位授予单位】：兰州大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R766;R587.1
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本文编号：1976057